Dermal Blood Flow Research Articles

Deoxycorticosterone-acetate salt-sensitive hypertension initiates with intracellular K+ and water loss

Background: Textbook teaching pretends that Na+-driven extracellular fluid and blood volume expansion may cause hypertension. We tested the alternative hypothesis, namely that K+ loss-driven intracellular volume contraction causes hypertension. Methods: We tested the effect of deoxycorticosterone acetate (DOCA; 25 mg pellet) in mice on low Na+ diet (0.02-0.03%) without (tap water), or with Na+ in their drinking water (1% NaCl or 1.44% NaHCO3). We measured BP with radio-telemetry, and analysed body Na+, K+, and water content 2, 6, and 12 days after initiation of DOCA treatment. We monitored food intake, solute and water excretion in urine and stool, and quantified renal and cutaneous blood flow by pulse-wave/laser Doppler spectroscopy. Results: DOCA NaCl treatment initially reduced intracellular K+ and water content, and elevated BP without accompanying Na+ retention. To re-hydrate the intracellular volume space, hypertensive DOCA NaCl−treated mice secondarily replaced lost intracellular K+ by Na+ solutes, increased fluid intake, reduced renal solute-free water clearance, constricted renal blood vessels, and reduced dermal blood flow. Normotensive DOCA NaHCO3-treated mice similarly lost intracellular K+, but immediately compensated by intracellular Na+ accumulation, and therefore experienced no intracellular volume contraction. Without prolonged under-hydration of their K+-space, DOCA NaHCO3-treated mice neither showed augmentation of renal or dermal water conservation, nor vasoconstriction and blood flow reduction, and their BP remained normal despite body Na+ excess. Conclusions: DOCA salt-sensitive hypertension is caused by K+-driven under-hydration, and not by Na+-driven over-hydration. The BP increase is explainable by secondary-adaptive multi-organ water conservation physiology, but not by Na+-driven water excretion physiology. National Medical Research Council (NMRC) of Singapore to the Duke-NUS Medical School, the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (Mars500-III; 50WB2024). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vascular read-out for TRP channel functionality on distal peripheral nerve endings in healthy men

BackgroundQuantification of the vasodilation after topical application of capsaicin or cinnamaldehyde is often implemented to indirectly assess Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1) or Ankyrin 1 (TRPA1) functionality respectively. This method has been well-established on the human forearm. However, to enable TRP functionality assessments in distal peripheral neuropathy, the vascular response upon TRP activation on dorsal finger skin was characterized. MethodsTwo doses of cinnamaldehyde (3 % and 10 % v/v) and capsaicin (300 μg and 1000 μg) were topically applied (20 μL) on the skin of the mid three proximal phalanges in 17 healthy men. The dose-response, and inter-hand and inter-period reproducibility of the dermal blood flow (DBF) increase was assessed using Laser Speckle Contrast Imaging (LSCI) during 60 min post-application. Linear mixed models explored dose-driven differences, whereas the intra-class correlation coefficient (ICC) estimated the reproducibility of the vascular response. ResultsBoth doses of cinnamaldehyde and capsaicin induced a robust, dose-dependent increase in DBF. The vascular response to cinnamaldehyde 10 % on finger skin, expressed as area under the curve, correlated well over time (ICC = 0.66) and excellently between hands (ICC = 0.87). Similarly, the response to capsaicin 1000 μg correlated moderately over time (ICC = 0.50) and well between hands (ICC = 0.73). ConclusionThe vascular response upon topical cinnamaldehyde and capsaicin application on finger skin is an alternative approach for measurements on forearm skin. Thereby, it is a promising vascular read-out to investigate the pathophysiology, and TRP involvement in particular, of specific peripheral neuropathic pain syndromes.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Does etodolac affect TRPA1 functionality invivo in human?

In preclinical research, etodolac, a non-steroidal anti-inflammatory drug, affected transient receptor potential ankyrin 1 (TRPA1) activation. Yet, whether the invitro interaction between etodolac and TRPA1 translates to altered TRPA1 functionality invivo in human remains to be investigated. A randomized, double-blinded, celecoxib-controlled study was conducted to assess the effect of etodolac on TRPA1-mediated dermal blood flow (DBF) changes on the forearm of 15 healthy, male volunteers aged between 18 and 45 years. Over four study visits, separated by at least five days wash-out, a single or four-fold dose of etodolac 200mg or celecoxib 200mg was administered orally. Two hours post-dose, TRPA1 functionality was evaluated by assessing cinnamaldehyde-induced DBF changes. DBF changes were quantified and expressed in Perfusion Units(PUs) using laser Doppler imaging during 60min post-cinnamaldehyde application. The corresponding area under the curve (AUC0-60min) was calculated as summary measure. Statistical analysis was performed using Linear mixed models with post-hoc Dunnett. Neither the single dose of etodolac nor celecoxib inhibited the cinnamaldehyde-induced DBF changes compared to no treatment (AUC0-60min±SEM of 17,751±1,514 PUs*min and 17,532±1,706 PUs*min vs. 19,274±1,031 PUs*min, respectively, both p=1.00). Similarly, also a four-fold dose of both compounds failed to inhibit the cinnamaldehyde-induced DBF changes (19,235±1,260 PUs*min and 19,367±1,085 PUs*min vs. 19,274±1,031 PUs*min, respectively, both p=1.00). Etodolac did not affect the cinnamaldehyde-induced DBF changes, suggesting that it does not alter TRPA1 functionality invivo in human.

Characterization of trigeminal C-fiber reactivity through capsaicin-induced release of calcitonin gene-related peptide.

We hypothesized that the response of trigeminal dermal blood flow (DBF) in the trigeminal system and consecutive expansion of flare response to capsaicin would differ from the somatosensory system (arm). We also investigated whether there are differences between patients with migraine and healthy controls (HC). Functional differences between the trigeminal and extracephalic somatosensory systems may partly explain the susceptibility for headaches in patients with migraine. Capsaicin-induced activation of nociceptive C-fibers in the skin is mainly mediated by calcitonin gene-related peptide (CGRP) and induces cutaneous vessel dilatation and flare response. Female patients with migraine (n=38) and age-matched HC (n=35) underwent DBF measurement at baseline and after topical capsaicin administration using laser speckle imaging. DBF before and after capsaicin stimulation was analyzed over ophthalmic nerve/maxillary nerve/mandibular nerve (V1/V2/V3) dermatomes and the forearm as an extracephalic control. Capsaicin-induced DBF increased more in the trigeminal dermatomes than on the forearm. The V1 dermatome showed a smaller increase of DBF in patients with migraine compared to HC. Our results suggest that the trigeminovascular system reacts differently from extracephalic areas, which may explain the trigeminal susceptibility to CGRP-mediated pain attacks. By demonstrating a different reactivity of the V1 dermatome in patients with migraine, our finding suggests that the first trigeminal branch is functionally different from the second and third branches; however, only in patients with migraine.

Histamine Skin Prick Tests: From Established Diagnostic Technique to Advanced Experimental Biomarker

Introduction: Skin prick tests have a long history as diagnostic and pharmacodynamic biomarker. Besides visual assessments of the wheal and flare, objective blood flow measurements using laser Doppler imaging (LDI) and laser speckle contrast imaging (LSCI) have been reported. In light of these advancements, an up-to-date characterization of the histamine-evoked response is worthwhile. Methods: A single-centre study was completed in healthy males. Two parameters were addressed: (1) dermal blood flow (DBF) within a 7.65-mm ring encircling the skin prick site (DBF_ring), and (2) surface area of the flare (AREA_flare). First, the dose response was assessed using placebo (0.9% sodium chloride) or histamine (histamine dihydrochloride 1, 3, or 10 mg/mL) skin pricks on the volar surface of subjects’ (n = 12) forearm. The DBF_ring was measured by LDI, and the AREA_flare by LDI and by ruler. Secondly, the inter-arm and inter-period reproducibility of the DBF_ring and AREA_flare, as evoked by histamine (10 mg/mL) and measured by LDI and LSCI, was examined (n = 14). Lastly, the effect of aprepitant (125 mg), ketotifen (1 mg), and a single (5 mg) and fourfold (20 mg) dose of desloratadine and levocetirizine on the histamine-induced (10 mg/mL) DBF_ring and AREA_flare was evaluated with LSCI (n = 13 or 12). Results: All three histamine doses induced a time-dependent vasodilation. Ruler recordings did not conclusively correlate with LDI assessments of the AREA_flare. The DBF_ring and AREA_flare were reasonably reproducible when measured by using LDI or LSCI, with negligible bias between arms and study periods and poor to moderate within-subject reproducibility (0.23 ≤ ICC ≤ 0.71). While the fourfold dose of desloratadine (p = 0.0041) and the single and fourfold dose of levocetirizine (p < 0.0001) managed to reduce the AREA_flare, only the fourfold dose of levocetirizine (p = 0.0052) reduced the DBF_ring. Conclusion: Caution is warranted when translating years of clinical experience with histamine skin prick tests to objective recordings of the associated changes in skin perfusion. Ruler and LDI assessments of the AREA_flare do not consistently correlate, and the reproducibility and histamine dependency of the measurements are not obvious. While 10 mg/mL histamine may be a good choice for qualitative diagnostic evaluations, a lower dose may be better suited to use as a quantitative biomarker.

Validation of laser doppler flowmetry to measure dermal blood flow of the pinnae in dogs with pinnal alopecia.

Laser Doppler flowmetry (LDF) is a noninvasive method of measuring regional blood flow in humans. However, this method has not been widely applied to measure blood flow in dogs. We hypothesised that LDF can measure changes in blood flow in canine pinnae accurately. The objectives were to determine whether LDF could accurately detect dermal blood flow changes in canine pinnae caused by haemodynamic drugs and characterize the dermal blood flow in dogs with pinnal alopecia. Sixteen laboratory-owned healthy dogs, 25 client-owned healthy control dogs and six dogs with pinnal alopecia suspected to be secondary to ischaemic dermatoses. Clinical doses of the haemodynamic drugs atropine, medetomidine and dibutyryl cyclic adenosine monophosphate (dBcAMP), as well as topical dBcAMP, were administered to healthy beagles. Subsequently, an LDF apparatus was attached to the pinnae to analyse changes in dermal blood flow. Finally, LDF was used to measure auricular dermal blood flow in dogs with pinnal alopecia compared to healthy dogs. Dermal blood flow increased after atropine injection, during dBcAMP infusion and after topical dBcAMP ointment application, and decreased after medetomidine injection. Auricular dermal blood flow (in mL/min/100 g tissue) was significantly (p < 0.05) lower in dogs with pinnal alopecia than in healthy dogs. Laser Doppler flowmetry is useful for measuring dermal blood flow in canine pinnae; it can be a noninvasive method to monitor ischaemic conditions of dog skin.

Trigeminovascular effects of propranolol in men and women, role for sex steroids

ObjectiveAssess whether propranolol modulates the trigeminovascular system in both men and women.MethodsWe investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to T max) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2–1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double‐blind, placebo‐controlled cross‐over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20–39 years old).ResultsDermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin‐induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients.InterpretationPropranolol (80 mg) inhibits capsaicin‐induced increases in dermal blood flow in a sex‐dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system.

Indocyanine Green Fluorescence Angiography in Minor Lower Extremity Amputations: A Useful Technique?

Complications remain despite conventional methods aimed at improving survivorship of lower extremity amputations. High rates of wound dehiscence, readmission, and revision surgery warrant the development of innovative methods to improve amputation survivorship. One such method employs the use of indocyanine green dye (ICG); an inert chemical injected intraoperatively which can be used to visualize dermal blood flow in real time. There is little objective data available to help guide the use of indocyanine green in limb salvage procedures. The present study compares a group of 31 patients undergoing minor lower extremity amputation with the use of indocyanine green with a control group of 62 patients in which traditional methods were used. Minimum follow-up of 9 months was obtained, leaving 93 patients in total for analysis. Success was defined as a healed amputation within 60 days of follow-up. Uneventful amputation healing occurred in 35.5% and 33.9% of indocyanine green and control patients, respectively. Overall, there was no significant difference in outcomes between groups (p = .965), or success versus failure (p = 1.0). Patient undergoing minor lower extremity amputation with the use of ICG fluorescence angiography did not have statistically inferior outcomes to patients who underwent amputations at the same level with traditional assessments of perfusion. Further research involving the use of this technique is warranted.

Galcanezumab modulates Capsaicin-induced C-fiber reactivity.

The vasodilatory calcitonin-gene related peptide (CGRP) is understood as pivotal mediator in migraine pathophysiology. Blocking CGRP with small molecules or monoclonal antibodies (CGRP-mAb) reduces migraine frequency. However, prescription of CGRP-mAbs is still regulated and possible predictive measures of therapeutic success would be useful. Using standardized capsaicin-induced dermal blood flow model, 29 migraine patients underwent a laser speckle imaging measurement before and after administration of galcanezumab. At both sessions dermal blood flow before and after capsaicin stimulation as well as flare size were analyzed over all three trigeminal branches and the volar forearm for extracranial control. Long-term measures were repeated in 14 patients after continuous treatment ranging from 6 to 12 months. Resting dermal blood flow remained unchanged after administration of galcanezumab. Capsaicin-induced dermal blood flow decreased significantly after CGRP-mAb in all tested areas compared to baseline and this was consistent even after 12 months of treatment. However, following galcanezumab administration, the flare size decreased only in the three trigeminal dermatomes, not the arm and was therefore specific for the trigemino-vascular system. None of these two markers distinguished between responders and non-responders. CGRP-mAb changed blood flow response to capsaicin stimulation profoundly and this effect did not change over a 12-month application. Neither capsaicin-induced flare nor dermal blood flow can be used as a predictor for treatment efficacy. These data suggest that the mechanism of headache development in migraine is not entirely CGRP-mediated.

Quantification of Dermal Microcirculatory Changes after Topical Administration of Capsaicin: A Randomized Placebo-Controlled Study in 46 Subjects

Background Dermal blood flow is crucial for wound healing and survival of flaps in dermatologic surgery. To improve flap viability in cases of compromised perfusion topical agents can easily be applied. The aim of this placebo-controlled study was to characterize changes of DBF in healthy subjects by quantitatively assessing perfusion dynamics after application of capsaicin to establish a reference for measurements at injured sites. Methods In 46 healthy subjects perfusion dynamics after local application with capsaicin and placebo was noninvasively assessed, determining cutaneous oxygen saturation, relative hemoglobin count and blood flow using an Oxygen-to-See device. Results A significant raise in superficial (162% p = 0.000) and deep (144%, p = 0.000) skin oxygenation after 30 min was provoked. A highly significant raise in measurements of flow and velocity was present in superficial (523%, p = 0.000) and deep (242%, p = 0.000) sites. Conclusion With the introduced model applied to observe changes in parameters of dermal blood flow in healthy subjects the authors can reliably monitor effects of topically administered capsaicin. This baseline can be used as reference for further studies in the settings of endangered flap survival or critically perfused wounds as has been proven in animal studies.

Optimization of capsaicin-induced dermal blood flow measurement by laser Doppler imaging in cynomolgus macaque.

Capsaicin is used in several areas of non-human primate research including allodynia and dermal blood flow (DBF). The capsaicin-induced DBF increase was measured using laser Doppler imaging (LDI), but this response is known to diminish upon repeated topical applications. Refinement of the experimental procedures could improve the rigor and reproducibility of the DBF migraine model. Optimal anatomical site in cynomolgus was determined, and conditions and experimental settings for DBF measurement using LDI were established. Then, two study design trial structures were compared. Medial thigh was the preferrable site, and an ethanol-Tween 20 formulation of capsaicin was desirable. A 1-week washout for contralateral side or 2-week washout for ipsilateral side was necessary to eradicate capsaicin desensitization. With the established technicality in DBF measurements in cynomolgus macaques, the capsaicin-induced DBF model may be utilized in translational medical research in developing migraine therapeutics.

Pain perception in women with menstrually-related migraine.

BackgroundCyclic hormonal fluctuations influence migraine incidence and severity. Previously, we described reduced menstrual cyclicity in estradiol levels and dermal blood flow reaction to capsaicin in female migraineurs. It is unclear whether pain perception in women with migraine is influenced by the menstrual cycle.MethodsWomen with menstrually-related migraine (n = 14), healthy age-matched controls (n = 10) and postmenopausal women (n = 15) were asked to grade trigeminal and non-trigeminal painful stimuli on a numeric pain rating scale on menstrual cycle day 19–21 (mid-luteal) and day 1–2 (early follicular).ResultsIn women with menstrually-related migraine, trigeminal pain remained low throughout the cycle. Controls showed increased trigeminal pain during the mid-luteal phase compared to the early follicular phase. Changes throughout the cycle were significantly different between women with MRM and controls.ConclusionThe compromised menstrual cyclicity of pain perception in women with menstrually-related migraine parallels our earlier findings on estradiol levels and dermal blood flow.

Development of AITC-induced dermal blood flow as a translational in vivo biomarker of TRPA1 activity in human and rodent skin.

Develop a translational assay of Transient Receptor Potential Ankyrin 1 (TRPA1) activity for use as a preclinical and clinical biomarker. Allyl isothiocyanate (AITC), capsaicin or citric acid were applied to ears of wildtype and Trpa1-knock out (Trpa1 KO) rats, and changes in dermal blood flow (DBF) were measured by laser speckle contrast imaging. In humans, the DBF, pain and itch responses to 5-20% AITC applied to the forearm were measured and safety was evaluated. Reproducibility of the DBF, pain and itch responses to topically applied 10% and 15% AITC were assessed at two visits separated by 13-15 days. DBF changes were summarized at 5-minute intervals as areas under the curve (AUC) and maxima. Intraclass correlation coefficient (ICC) was calculated to assess arm-arm and period-period reproducibility. AITC- and citric acid-induced DBF were significantly reduced in Trpa1 KO rats compared to wildtype (90 ± 2% and 65 ± 11% reduction, respectively), whereas capsaicin response did not differ. In humans, each AITC concentration significantly increased DBF compared to vehicle with the maximal increase occurring 5 minutes post application. Ten percent and 15% AITC were selected as safe and effective stimuli. AUC from 0 to 5 minutes was the most reproducible metric of AITC-induced DBF across arms (ICC = 0.92) and periods (ICC = 0.85). Subject-reported pain was more reproducible than itch across visits (ICC = 0.76 vs 0.17, respectively). AITC-induced DBF is a suitable target engagement biomarker of TRPA1 activity for preclinical and clinical studies of TRPA1 antagonists.

Sumatriptan Does Not Antagonize CGRP‐Induced Symptoms in Healthy Volunteers

Previous attempts to develop a pragmatic human model for testing new anti-migraine drugs, have failed. Calcitonin gene-related peptide (CGRP) induces a mild headache in healthy volunteers and migraine-like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP-induced symptoms in an attempt to validate CGRP-induced headache as a model for drug testing. Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP on 2 separate days. The participants were pretreated with sumatriptan 1 day and with placebo the other day in a randomized double-blind cross-over fashion. During the infusion, a questionnaire about headache and side effects was administered. Electrocardiography, heart rate, blood pressure, dermal blood flow, and diameter of peripheral arteries were monitored during the infusion. Participants were carefully instructed to fill out a headache questionnaire at home until 12hours after the infusion start. Primary endpoints are difference between the sumatriptan day and the placebo day in area under the headache score curve (AUC) 0-2hours after infusion start and in headache intensity 2hours after infusion start. The study was conducted at the Danish Headache Center in Glostrup, Denmark. CGRP-induced headache in 86% (25/29) of the participants on the sumatriptan day and in 96% (28/29) of the participants on the placebo day. There was no difference in AUCheadache, 0-2hours between the days (P=.794). There was a statistically significant decrease in mean atrial pressure (MAP) over time on both days with a16.2% reduction on the sumatriptan day and a 14.8% reduction on the placebo day (P<.001) and a statistically significant increase in heart rate (HR) over time on both days (from mean 57.5 at baseline to mean 105.4 at 120minutes on the sumatriptan day and from mean 60.2 at baseline to 105.8 at 120minutes on the placebo day, P<.001). The diameter of peripheral arteries increased statistically significant on both days (P<.001). Sumatriptan does not influence headache score, accompanying symptoms or other symptoms induced by CGRP. Furthermore, a 2-hour CGRP infusion causes a wide range of side effects and does not induce more headache than the usual 20-minute infusion. Thus, the prolonged infusion of CGRP in healthy volunteers is not a valid and pragmatic model for testing new anti-migraine drugs.

Laser speckle contrast imaging, the future DBF imaging technique for TRP target engagement biomarker assays

A comparison was made between the established laser Doppler imaging (LDI) technique and the more recently developed laser speckle contrast imaging (LSCI) method to measure changes in capsaicin- and cinnamaldehyde-induced dermal blood flow (DBF) as an indicator of TRPV1 and TRPA1 activation, respectively. MethodsCapsaicin (1000 μg/20 μl) and cinnamaldehyde (10%) solutions were applied on the forearm of 16 healthy male volunteers, alongside their corresponding vehicle solutions. Pre challenge and 10, 20, 30, 40 and 60 min post challenge application, changes in DBF were assessed with the LSCI technique, followed by LDI. The area under the curve from 0 to 60 min (AUC0–60) post capsaicin and cinnamaldehyde application was calculated as a summary measure of the response. Correlation between the LDI and LSCI instrument was assessed using a simple linear regression analysis. Sample size calculations (SSC) were performed for future studies using either the LDI or LSCI technique. ResultsHigher arbitrary perfusion values were obtained with LDI compared to LSCI, yet a complete discrimination between the challenge and vehicle responses was achieved with both techniques. A strong degree of correlation was observed between LDI and LSCI measurements of the capsaicin- (R = 0.84 at Tmax and R = 0.92 for AUC0–60) and cinnamaldehyde-induced (R = 0.78 at Tmax and R = 0.81 for AUC0–60) increase in DBF. SSC revealed that LSCI requires considerably less subjects to obtain a power of 80% (about 15 versus 27 subjects in case of capsaicin and 7 versus 13 for cinnamaladehyde). ConclusionsThe LSCI technique was identified as the preferred method to capture capsaicin- and cinnamaldehyde-induced changes in DBF. Besides its reduced variability, the shorter scan time provides a major advantage, allowing real-time DBF measurements.

The color of skin: red diseases of the skin, nails, and mucosa

Red color is pervasive in local and systemic skin conditions. It is a color that often reflects variations of dermal blood flow and extends beyond the rubor and calor of inflammation. The pathophysiology of red skin involves remote and local chemical mediators that dilate arteriolar smooth muscle and increase blood flow to superficial vessels and capillary beds. Incident light hits hemoglobin, which preferentially absorbs light of shorter wavelengths, such as blue, and reflects warmer colors. Due to its pervasiveness and consistency, red color is a useful descriptive factor in helping narrow a differential diagnosis. Red skin disorders include a variety of conditions involving endocrine mediators, cardiovascular responses, and the disruption of the skin barrier. An understanding of the blood’s role in these disorders equips clinicians to generate differential diagnoses through the lens of pathophysiology. Dermatologists can improve management by considering red skin as part of systemic disease rather than as an isolated incident.

Transdermal Detection of Hydrogen Sulfide in Humans

We have developed a novel approach to measure circulating hydrogen sulfide (H2S) non‐invasively as a potential way to diagnose and monitor endothelial dysfunction and peripheral artery disease (PAD). PAD is a life‐threatening condition caused by arterial constriction and obstruction of blood flow leading to limb ischemia. Current methods to diagnose and monitor PAD lack sensitivity, are expensive, and technically difficult. Recent studies indicate that decreased H2S production is an underlying cause of PAD. Reduced plasma H2S also correlates with endothelial dysfunction in individuals with untreated hypertension, diabetes, sleep apnea, and other cardiovascular diseases. The Transdermal Gas Sensor (TAGS) device was designed to measure transdermal H2S to test the hypothesis that the diffusion rate (and therefore gas phase concentration) of H2S is directly proportional to dermal blood flow in individuals without endothelial disease. Healthy volunteers between the ages of 21–65 were recruited. Exclusion criteria included subjects currently treated for hypertension, hyperlipidemia, and diabetes. Smokers and pregnant women were also excluded. We observed a linear association between TAGS readings and Laser Speckle Contrast Imaging (LSCI), a gold standard measure of skin blood flow, when readings were adjusted for age in the model (r = 0.5717, p = 0.0132, n = 18). Therefore the TAGS device is not inferior to LSCI in measuring skin blood flow in healthy individuals using a non‐inferiority margin of 5 (p = 0.0394). The TAGS device has the potential, therefore, to serve as a more sensitive, economical, and easy to use diagnostic tool to use H2S detection as a predictor of dermal blood flow.Support or Funding InformationNSF: R41 NSF FP00000502. NHLBI: R41HL121871This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P131: Transdermal Detection of Low Concentrations of Hydrogen Sulfide

We report here a novel approach to measure circulating hydrogen sulfide (H 2 S) non-invasively as a potential way to diagnose and monitor endothelial dysfunction and peripheral artery disease (PAD). PAD is a life-threatening condition caused by arterial constriction and obstruction of blood flow leading to limb ischemia. Current methods to diagnose and monitor PAD lack sensitivity, are expensive, and technically difficult. Recent studies indicate that decreased H 2 S production is an underlying cause of PAD. Also, reduced plasma H 2 S correlates with endothelial dysfunction in individuals with untreated hypertension, diabetes, sleep apnea and other cardiovascular diseases. The TAGS device was designed to measure transdermal H 2 S to test the hypothesis that the diffusion rate (and therefore gas phase concentration) of H 2 S is directly proportional to dermal blood flow. Healthy volunteers between the ages of 21-65 were recruited. Exclusion criteria included subjects currently treated for hypertension, hyperlipidemia, and diabetes. Smokers and pregnant women were also excluded. We demonstrate that H 2 S can be detected in healthy volunteers (n=11) at 10.8 part per billion (ppb). Interestingly, there is a positive correlation between age and TAGS readings in male volunteers (r=0.614; n= 6) and a negative correlation in female volunteers (r=0.482, n=5). The TAGS device has the potential, therefore, to serve as a more sensitive, economical, and easy to use diagnostic tool to detect H 2 S and predict dermal blood flow.

RVCL-S and CADASIL display distinct impaired vascular function.

We aimed to evaluate the role of endothelial-dependent and endothelial-independent vascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), both cerebral small vessel diseases are considered models for stroke, vascular dementia, and migraine. RVCL-S (n = 18) and CADASIL (n = 23) participants with TREX1 and NOTCH3 mutations, respectively, were compared with controls matched for age, body mass index, and sex (n = 26). Endothelial function was evaluated by flow-mediated vasodilatation, and endothelial-independent vascular reactivity (i.e., vascular smooth muscle cell function) was assessed by dermal blood flow response to capsaicin application. Flow-mediated vasodilatation was decreased in participants with RVCL-S compared with controls (2.32% ± 3.83% vs 5.76% ± 3.07% change in diameter, p = 0.023) but normal in participants with CADASIL. Vascular smooth muscle cell function was reduced in participants with CADASIL compared with controls (maximal dermal blood flow increase at 40 minutes after capsaicin: 1.38 ± 0.88 vs 2.22 ± 1.20 arbitrary units, p = 0.010) but normal in participants with RVCL-S. We identified endothelial dysfunction in RVCL-S and confirmed impaired vascular smooth muscle cell relaxation in CADASIL. Our findings may prove to be biomarkers for disease progression in both monogenic cerebral small vessel diseases and improve mechanistic insight in their pathophysiology. This may help in understanding common neurovascular disorders, including stroke, dementia, and migraine.