Forearm Blood Flow Measurements Research Articles

Changes in vascular function during breast cancer treatment.

AimsBreast cancer (BC) survivors are at increased risk of cardiovascular disease. We evaluated whether chemotherapy induces early or late vascular dysfunction in vivo.MethodsEarly‐stage BC patients (n = 33) underwent measurements of forearm blood flow (FBF), 24‐hour blood pressure (BP), aortic pulse wave velocity and inflammatory markers before (T0), 14 days after (T1) and 12 months after (T2) chemotherapy. FBF was assessed during intra‐arterial infusion of acetylcholine (ACh), ACh during simultaneous nitric oxide synthase inhibition with L‐NG‐monomethyl arginine, and during infusion of sodium nitroprusside. Controls matched by age and menopausal status were examined for baseline comparison.ResultsAt T0, absolute FBF in the BC patients did not differ from controls. At T1, ACh‐induced absolute FBF was higher compared to T0. ACh‐induced FBF decreased significantly at T2, evaluated as area under the dose–response curve, and when corrected for FBF in the contralateral arm (FBF ratio at T0: 4.05, 95% confidence interval [2.54; 5.74] and T2: 2.77 [2.41; 3.50]), without difference evident during L‐NG‐monomethyl arginine infusion. FBF during sodium nitroprusside infusion remained unchanged. Pulse wave velocity and BP remained unchanged. Asymmetric dimethylarginine (T0: 0.68 μmol/L ± 0.17, T1: 0.75 μmol/L ± 0.16) and the inflammation‐related biomarkers Cd163 (T0: 1.86 mg/L [1.68; 2.05], T1: 2.04 mg/L [1.76; 2.4]) and Cd206 (T0: 0.22 mg/L [0.19; 0.26], T1: 0.27 mg/L [0.23; 0.30]) all increased significantly at T1, but returned to baseline values at T2. L‐arginine was significantly increased at both T1 (78.5 μmol/L [68.9; 86.6]) and T2 (76.8 μmol/L [66.9; 90.6]), compared to T0 (59.6 μmol/L [53.7; 68.0]).ConclusionChemotherapy for BC seems associated with early amplification of endothelium‐dependent vasodilation and inflammation. One year after chemotherapy, microvascular dysfunction persists in terms of reduced NO‐dependent vasodilation without alterations in BP or arterial stiffness.

Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude – A randomised controlled trial (Xtreme Alps)

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate ‘placebo’. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 μM) and at day 5 (D5) of high altitude (22.9 vs 84.3 μM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 μM SL, 0.31 vs. 0.41 μM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m.

Cardiac resynchronization therapy restores muscular metaboreflex control.

The muscular metaboreflex, whose activation regulates blood flow during isometric and aerobic exercise, is blunted in patients with heart failure (HF), and cardiac resynchronization therapy (CRT) may restore this regulatory reflex. To evaluate metaboreflex responses after CRT. Thirteen HF patients and 12 age-matched healthy control subjects underwent the following evaluations (pre- and post-CRT implantation in the patient group): (a) heart rate, blood pressure, and forearm blood flow measurements; (b) muscle sympathetic nerve activity (MSNA) evaluation; and (c) peak oxygen consumption (VO2peak ). Examinations were performed at rest, during moderate isometric exercise (IE), and during forearm ischemia (metaboreflex activation). The primary outcome was the increment in MSNA during limb ischemia compared to the rest moment (ΔMSNA rest to metaboreflex activation). After CRT, rest MSNA decreased in the HF participants: 50.4 ± 9.2 bursts/min pre-CRT vs 34.0 ± 14.4 bursts/min post-CRT, P = .001, accompanied by an improvement in systolic blood pressure and in rate-pressure product. MSNA during limb ischemia decreased: 56.6 ± 11.5 bursts/min pre-CRT vs 43.6 ± 12.7 bursts/min post-CRT, P = .001, and the ΔMSNA rest to metaboreflex activation increased: 0% (interquartile range [IQR)], -7 to 9) vs 13% (IQR, 5-30), P = .03. An augmentation of mean blood pressure during limb ischemia post-CRT was noticed: 94 mmHg (IQR, 81-104) vs 110 mmHg (IQR, 100-117), P = .04. CRT improved VO2peak , and this improvement was correlated with diminution in ΔMSNA pre- to post-CRT at rest moment (rs = -0.74, P = .006). CRT provides metaboreflex sensitization and MSNA enhancement. The restoration of sympathetic responsiveness correlates with the improvement in functional capacity.

GLP-1 Is a Coronary Artery Vasodilator in Humans.

BackgroundThe mechanism underlying the beneficial cardiovascular effects of the incretin GLP‐1 (glucagon‐like peptide 1) and its analogues in humans is elusive. We hypothesized that activating receptors located on vascular smooth muscle cells to induce either peripheral or coronary vasodilatation mediates the cardiovascular effect of GLP‐1.Methods and ResultsTen stable patients with angina awaiting left anterior descending artery stenting underwent forearm blood flow measurement using forearm plethysmography and post–percutaneous coronary intervention coronary blood flow measurement using a pressure‐flow wire before and after peripheral GLP‐1 administration. Coronary sinus and artery bloods were sampled for GLP‐1 levels. A further 11 control patients received saline rather than GLP‐1 in the coronary blood flow protocol. GLP‐1 receptor (GLP‐1R) expression was assessed by immunohistochemistry using a specific GLP‐1R monoclonal antibody in human tissue to inform the physiological studies. There was no effect of GLP‐1 on absolute forearm blood flow or forearm blood flow ratio after GLP‐1, systemic hemodynamics were not affected, and no binding of GLP‐1R monoclonal antibody was detected in vascular tissue. GLP‐1 reduced resting coronary transit time (mean [SD], 0.87 [0.39] versus 0.63 [0.27] seconds; P=0.02) and basal microcirculatory resistance (mean [SD], 76.3 [37.9] versus 55.4 [30.4] mm Hg/s; P=0.02), whereas in controls, there was an increase in transit time (mean [SD], 0.48 [0.24] versus 0.83 [0.41] seconds; P<0.001) and basal microcirculatory resistance (mean [SD], 45.9 [34.7] versus 66.7 [37.2] mm Hg/s; P=0.02). GLP‐1R monoclonal antibody binding was confirmed in ventricular tissue but not in vascular tissue, and transmyocardial GLP‐1 extraction was observed.Conclusions GLP‐1 causes coronary microvascular dilation and increased flow but does not influence peripheral tone. GLP‐1R immunohistochemistry suggests that GLP‐1 coronary vasodilatation is indirectly mediated by ventricular‐coronary cross talk.

Atorvastatin combined with ticagrelor prevent ischemia-reperfusion induced vascular endothelial dysfunction in healthy young males – A randomized, placebo-controlled, double-blinded study

BackgroundAtorvastatin and ticagrelor have been shown to prevent against tissue injury in animals. It is unclear if these beneficial effects are also detectable in humans. We studied the effect of high-dose atorvastatin combined with ticagrelor loading on endothelial dysfunction in a model of forearm vascular ischemia-reperfusion (IR) injury. Methods32 healthy subjects (n=16 per group) were enrolled in this randomized, placebo-controlled, double-blinded trial. Forearm blood flow (FBF) measurements in response to increasing intra-arterial doses of the vasodilator acetylcholine (ACh; endothelium-dependent agonist) and glyceryltrinitrate (GTN; endothelium-independent) were performed before and after a cuff-induced 20min forearm ischemia, respectively. FBF reactivity was assessed prior to any pharmacological intervention and after 14days intake of 80mg atorvastatin once daily or placebo, followed by an oral loading dose of 180mg ticagrelor. In addition, lipoprotein parameters and platelet aggregation were evaluated. ResultsTicagrelor loading mitigated ischemia-induced endothelial dysfunction and in combination with repeated atorvastatin dosing the response to ACh during reperfusion was completely normalized (FBF AChAUC ratio post- vs. pre-ischemia: 0.81 [ticagrelor] vs. 1.04 [atorvastatin+ticagrelor]; P=0.001). As expected, GTN-induced vasodilation was not affected by IR injury. Atorvastatin significantly reduced total and low density lipoprotein cholesterol concentrations, while high density lipoprotein cholesterol and triglyceride levels remained unchanged. ConclusionChronic atorvastatin treatment combined with ticagrelor loading prevents against endothelial dysfunction after acute forearm ischemia. Ticagrelor alone mitigated the impaired endothelium-dependent FBF response as compared to no pharmacological intervention. Clinical trial registrationURL: https://clinicaltrials.gov. Unique identifier: NCT02910778.

Altered Blood Flow Response to Small Muscle Mass Exercise in Cancer Survivors Treated With Adjuvant Therapy.

BackgroundAdjuvant cancer treatments have been shown to decrease cardiac function. In addition to changes in cardiovascular risk, there are several additional functional consequences including decreases in exercise capacity and increased incidence of cancer‐related fatigue. However, the effects of adjuvant cancer treatment on peripheral vascular function during exercise in cancer survivors have not been well documented. We investigated the vascular responses to exercise in cancer survivors previously treated with adjuvant cancer therapies.Methods and ResultsPeripheral vascular responses were investigated in 11 cancer survivors previously treated with adjuvant cancer therapies (age 58±6 years, 34±30 months from diagnosis) and 9 healthy controls group matched for age, sex, and maximal voluntary contraction. A dynamic handgrip exercise test at 20% maximal voluntary contraction was performed with simultaneous measurements of forearm blood flow and mean arterial pressure. Forearm vascular conductance was calculated from forearm blood flow and mean arterial pressure. Left ventricular ejection time index (LVETi) was derived from the arterial pressure wave form. Forearm blood flow was attenuated in cancer therapies compared to control at 20% maximal voluntary contraction (189.8±53.8 vs 247.9±80.3 mL·min−1, respectively). Forearm vascular conductance was not different between groups at rest or during exercise. Mean arterial pressure response to exercise was attenuated in cancer therapies compared to controls (107.8±10.8 vs 119.2±16.2 mm Hg). LEVTi was lower in cancer therapies compared to controls.ConclusionsThese data suggest an attenuated exercise blood flow response in cancer survivors ≈34 months following adjuvant cancer therapy that may be attributed to an attenuated increase in mean arterial pressure.

Short-Term Angiotensin Subtype 1 Receptor Blockade Does Not Alter the Circulatory Responses to Sympathetic Nervous System Modulation in Healthy Volunteers Before and During Sevoflurane Anesthesia: Results of a Pilot Study

The mechanism of perioperative hypotension in patients taking an angiotensin-receptor blocker up to the time of surgery remains unclear. This study tested the hypothesis that short-term angiotensin-receptor blocker treatment attenuated the sympathetic and vascular responses to autonomic stimuli in volunteers undergoing anesthesia. Randomized, crossover, blinded, pilot design. Zablocki Veterans Affairs Medical Center, Milwaukee, WI. The study comprised 8 male and 6 female healthy, young volunteers (age 23±1.2 years [mean±standard error of the mean]). Volunteers were studied after receiving oral placebo or 50 mg of losartan (angiotensin-receptor blocker) for 3 days before each test day. The effectiveness of angiotensin-receptor blocker treatment was confirmed using the mean arterial blood pressure response to intravenous angiotensin II (1-µg bolus). Eight volunteers underwent direct mean arterial pressure and forearm bloodflow measurements during conscious baseline, a cold pressor test, induction of anesthesia, tracheal intubation, maintenance of anesthesia with 1 minimum alveolar concentration of sevoflurane, and airway irritation with 12% desflurane. Six volunteers experienced mean arterial pressure responses to 0.1 mg of phenylephrine at baseline and during 1 minimum alveolar concentration of sevoflurane. Comparisons were made over time and across groups. Angiotensin-receptor blocker treatment significantly reduced-mean arterial pressure and forearm vascular resistance (forearm blood flow/mean arterial pressure) over time and blocked the mean arterial pressure response to angiotensin-II challenge. The changes in mean arterial pressure and forearm vascular resistance in response to all stressors did not differ between treatments. Mean arterial pressure increases from phenylephrine were preserved. In healthy, young volunteers, sympathetically-mediated responses from the short-term use of an angiotensin-receptor blocker were not altered and most likely did not contribute to perioperative hypotension during the intraoperative period.

The Impact of Acute Isocapnic Hypoxia on Reactive Hyperemia in Young, Healthy Humans

Acute hypoxic exposure results in a number of significant physiological responses, including vasodilation in vascular beds of the skeletal muscle. The objective of this study was to investigate the effects of acute hypoxic exposure on microvascular function in young healthy humans, as determined by reactive hyperemia (RH). We first hypothesized that brief exposure to isocapnic hypoxia just prior to arterial occlusion would exaggerate the reactive hyperemic response, given hypoxic vasodilation may cause an increased oxygen mismatch. Second, we hypothesized continuous isocapnic hypoxia prior to and throughout arterial occlusion would attenuate the reactive hyperemic response given chronic exposure has been linked to vascular dysfunction. We tested subjects between the ages of 20 and 23 (n=6) with three counterbalanced trials: control, prior hypoxic exposure, and prolonged hypoxic exposure. Subjects were monitored for end‐tidal CO2 (gas analyzer), O2 saturation (pulse oximetry), heart rate (ECG) and blood pressure (sphygmomanometry). Forearm blood flow (FBF) measurements using venous occlusion plethysmography were made prior to and following 5 minutes of forearm ischemia (RH). During experimental trials, subjects breathed hypoxic gas to decrease arterial O2 saturation to ~85% and isocapnia was maintained via a rebreathe system. Peak RH FBF was slightly increased after brief hypoxic exposure compared to normoxia (43.2±4.2 vs 40.3±6.2 ml/dl/min). However, in continuous hypoxia, peak RH FBF (39.6±3.9 ml/dl/min) was similar to normoxia. The total area under the curve during RH was similar in all three trials (normoxia: 156±9 ml; brief: 152±6 ml; continuous: 154±14 ml). Continuous hypoxia resulted in increased heart rate as compared to brief hypoxia and normoxia. The present results suggest that a brief period of hypoxia prior to occlusion does not impair RH responses. In addition, in young healthy humans, RH responses are preserved following continuous hypoxia throughout occlusion.Support or Funding InformationUniversity of Dayton‐ Research Council Grant‐In‐Aid; University Honors Berry Summer Thesis Program

Effects of Chemotherapy and Radiation Exposure on Brachial Artery Blood Flow during Dynamic Handgrip Exercise

Chemotherapy and radiation cancer treatments have been shown to alter peripheral cardiovascular function. Therefore, the purpose of this study was to investigate if the vascular responses to dynamic handgrip exercise are blunted in individuals who have undergone chemotherapy and/or radiation treatment. To date, 1 cancer survivor (CS) and 1 healthy control (HC) have completed two dynamic handgrip exercise protocols at relative (10 and 20% maximal voluntary contraction (MVC)) and absolute (3 and 9 kg) workloads. Simultaneous measurements of forearm blood flow (FBF; Doppler Ultrasound), and mean arterial pressure (MAP) were taken during each of the workloads. Forearm vascular conductance (FVC) was calculated from MAP and FBF. Plasma concentrations of endothelial microparticles (EMPs) which are suggestive of apoptotic and activated endothelial cells (CD31+/CD42b‐ and CD62E+ EMPs, respectively) were isolated from venous blood samples. Preliminary results: FBF was decreased in CS compared to HC at: 10% MVC (111.72 vs. 228.17 ml min‐1) and 20% MVC (148.60 vs. 362.53 ml min‐1). FVC was reduced in CS when compared to HC at: 10% MVC (107.65 vs. 205.32 ml min‐1 100 mmHg‐1) and 20% MVC (135.35 vs. 287.64 ml min‐1 100 mmHg‐1). During absolute workloads FBF and FVC of the CS compared to HC was similar at 3 kg (143.91 vs. 135.26 ml min‐1 and 162.33 vs. 124.42 ml min‐1 100 mmHg‐1, respectively), but less at 9 kg (156.11 vs. 307.42 ml min‐1 and 155.24 vs. 263.54 ml min‐1 100 mmHg‐1, respectively). Due to time constraints plasma EMP concentrations are unavailable at this time. In conclusion, chemotherapy and radiation treatment in cancer survivors results in alterations to exercise blood flow regulation during dynamic exercise.

Stimulation of Nitric Oxide Synthase Activity By Plasma Apolipoproteins: a Biomarker of Endothelial Function in Adults with Sickle Cell Disease

Nitric oxide (NO) plays a critical role in maintaining basal vascular tone and regulating blood flow. Many factors, including shear stress and endogenous ligands such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1), stimulate the activity of endothelial nitric oxide synthase (eNOS). We have developed a bioassay that measures stimulation of NOS activity by soluble factors in unfractionated human plasma in cultured human endothelial cells using a sensitive NOS activity assay with radiolabeled substrate.The addition of 1% human plasma to the culture medium stimulates NOS activity 1.5-fold over background, with a linear response up to 10% plasma, which activates NOS 5.5-fold. We have concluded from several lines of evidence that this NOS-inducing activity in human plasma comes from high-density lipoprotein (HDL): The activity is heat-labile and sensitive to reducing agents; it is precipitable by ammonium sulfate and elutes as a broad peak on molecular exclusion and anion exchange columns; by immunoblot, the active fractions have large amounts of apolipoproteins apoA-I, apoE and paroxonase-1. We find that plasma from an apoA-I null mouse shows less stimulation of NOS activity in our bioassay than plasma from a wild type mouse and apoA-I transgenic mouse (p=0.06, Brown-Forsythe test; p=0.04, post-test for linear trend; see figure). Purified HDL fractions stimulate NOS activity four-fold, equivalent to unfractionated plasma, but further subfractionation of HDL components extinguishes its ability to activate NOS.Remarkably, higher than median NOS-stimulating activity in our bioassay was associated with endothelial-dependent blood flow, detected by venous occlusion strain gauge plethysmography measurement of forearm blood flow induced by graded infusions of acetylcholine into the brachial artery in adults with sickle cell anemia (p=0.0013, two-way ANOVA, see figure). The NOS-stimulating activity in patient plasma also correlated with the plasma apoA-I level (Spearman r=0.64, p=0.0012).In summary, our results suggest that circulating functional apoA-I and possibly other apolipoproteins, regulate NO production and endothelial function in adults with sickle cell disease, which is consistent with previous lines of evidence published by other investigators in subjects without sickle cell disease. Most strikingly, our plasma NOS stimulation assay appears to provide a useful research biomarker for endothelial function, applicable to frozen archived plasma biospecimens. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PO-0344 Development Of A Paediatric Model To Mimic Reduced Cutaneous Blood Flow: Validation Using Laser Doppler And Photoplethysmography

Background Skin blood flow is highly variable accounting for 5–33% of cardiac output (Kenny 2011), and is often one of the first organs to change during early shock. In children, capillary refill time (CRT) is a crucial component of cardiovascular assessment and, despite marked variability, it remains a useful predictor of significant illness in children (Tibby 1999, Craig 2010). To allow development of new technologies to assess cutaneous blood flow a simple but valid model of reduced perfusion is required. Aims 1) Develop an acceptable paediatric model for reduced cutaneous perfusion, 2) Assess the ability of laser Doppler (LD) and green light photoplethysmography (gPPG) to detect these changes. Participants and methods Healthy children (5–17 years) were recruited. Simultaneous forearm LD blood flow and gPPG CRT measurements were obtained at baseline (room temperature) and during localised cooling of the arm (4 o C microenvironment). gPPG CRT was measured using a reflectance mode gPPG coupled with an automated pressure application system. Results Ten children completed the study over a typical timeframe of 45 min. Median LD blood flow decreased significantly from baseline during the cold exposure (P Conclusion This model appears to be both feasible and acceptable to children. Confirmation of reduced blood flow is observed using LD. Our automated CRT utilising gPPG appears useful in this model. After additional validation, the suitability and usefulness of automated CRT could be assessed in paediatric clinical trials with a view to improving recognition of early shock.

Individual susceptibility to hypoperfusion and reductions in exercise performance when perfusion pressure is reduced: evidence for vasodilator phenotypes.

The primary objective of this study was to determine whether cardiovascular compensatory response phenotypes exist in the face of a reduced perfusion pressure challenge to exercising muscle oxygen delivery (O2D), and whether these responses might be exercise intensity (EI) dependent. Ten healthy men (19.5 ± 0.4 yr) completed two trials of progressive forearm isometric handgrip exercise to exhaustion (24.5 N increments every 3.5 min) in each of forearm above and below heart level [forearm arterial perfusion pressure (FAPP) difference of 29.5 ± 0.97 mmHg]. At the end of each EI, measurements of forearm blood flow (FBF; ml/min) via brachial artery Doppler and echo ultrasound, mean arterial blood pressure (MAP; mmHg) via finger photoplethysmography, and exercising forearm venous effluent via antecubital vein catheter revealed distinct cardiovascular response groups: n = 6 with compensatory vasodilation vs. n = 4 without compensatory vasodilation. Compensatory vasodilators were able to blunt the perfusion pressure-evoked reduction in submaximal O2D in the arm-above-heart condition, whereas nonvasodilators did not (-22.5 ± 13.6 vs. -65.4 ± 14.1 ml O2/min; P < 0.05), and in combination with being able to increase O2 extraction, nonvasodilators defended submaximal V̇o2 and experienced less of an accumulated submaximal O2D deficit (-80.7 ± 24.7 vs. -219.1 ± 36.0 ml O2/min; P < 0.05). As a result, the compensatory vasodilators experienced less of a compromise to peak EI than nonvasodilators (-24.5 ± 3.5 N vs. -52.1 ± 8.9 N; P < 0.05). In conclusion, in the forearm exercise model studied, vasodilatory response phenotypes exist that determine individual susceptibility to hypoperfusion and the degree to which aerobic metabolism and exercise performance are compromised.

Seasonal variation of plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma

Background: Higher plasma concentrations of catecholamines in winter than in summer are established; whether this impacts plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. Objective: In this study, we examined seasonal variations in plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming (‘arterialization’ of venous blood) on blood flow and measured concentrations. Methods: Measurements of plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for measurements of plasma metanephrines and forearm blood flow before and after forearm warming. Results: There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, plasma concentrations of normetanephrine were higher (P!0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P!0.0001). These differences resulted in a twofold higher (PZ0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (PZ0.0010). Forearm warming increased blood flow and lowered (PZ0.0020) plasma normetanephrine concentrations. Conclusions: Plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

Seasonal variation in plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma

Higher plasma concentrations of catecholamines in winter than in summer have been established, but whether this impacts the plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. In this study, we examined seasonal variations in the plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming ('arterialization' of venous blood) on blood flow and measured concentrations. The measurements of the plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for the measurements of plasma metanephrines and forearm blood flow before and after forearm warming. There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, the plasma concentrations of normetanephrine were higher (P<0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P<0.0001). These differences resulted in a twofold higher (P=0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (P=0.0010). Forearm warming increased blood flow and lowered (P=0.0020) plasma normetanephrine concentrations. The plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

Exercise training improves endothelial function in resistance arteries of young prehypertensives

Prehypertension is associated with reduced conduit artery endothelial function and perturbation of oxidant/antioxidant status. It is unknown if endothelial dysfunction persists to resistance arteries and if exercise training effects oxidant/antioxidant balance in young prehypertensives. We examined resistance artery function using venous occlusion plethysmography measurement of forearm (FBF) and calf blood flow (CBF) at rest and during reactive hyperemia, as well as lipid peroxidation (8-iso-PGF2α) and antioxidant capacity (Trolox-equivalent antioxidant capacity; TEAC) before and after exercise intervention or time-control. Forty-three unmedicated prehypertensive and fifteen matched normotensive time-controls met screening requirements and participated in the study (age: 21.1±0.8 years). Prehypertensive subjects were randomly assigned to resistance exercise training (PHRT; n=15), endurance exercise training (PHET; n=13) or time-control groups (PHTC; n=15). Treatment groups exercised 3 days per week for 8 weeks. Peak and total FBF were lower in prehypertensives than normotensives (12.7±1.2 ml/min/100ml tissue and 89.1±7.7 ml/min/100ml tissue vs. 16.3±1.0 ml/min/100ml tissue and 123.3±6.4 ml/min/100ml tissue, respectively; p<0.05). Peak and total CBF were lower in prehypertensives than normotensives (15.3±1.2 ml/min/100ml tissue and 74±8.3 ml/min/100ml tissue vs. 20.9±1.4 ml/min/100ml tissue and 107±9.2 ml/min/100ml tissue, respectively; p<0.05). PHRT and PHET improved humoral measures of Trolox-equivalent antioxidant-capacity (TEAC) (+24% and +30%) and 8-iso-PGF2α (−43% and −40%, respectively; p<0.05). This study provides evidence that young prehypertensives exhibit reduced resistance artery endothelial function and that short term (8weeks) resistance or endurance training are effective in improving resistance artery endothelial function and oxidant/antioxidant balance in young prehypertensives.

Decreased Permeability Surface Area for Glucose in Obese Women with Postprandial Hyperglycemia: No Effect of Phosphodiesterase-5 (PDE-5) Inhibition

Insulin-mediated microvascular recruitment is recognized as a potential mechanism contributing to insulin resistance. In this study, we compared a marker of microvascular function, the permeability surface area for glucose (PS(glu)), and forearm glucose uptake after an OGTT in obese women with impaired glucose metabolism and healthy lean nondiabetic women, with the aim to characterize whether decreased permeability surface area for glucose or decreased glucose uptake may contribute to postprandial hyperglycemia in the obese group. In addition, we evaluated whether the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, in a randomized double blind placebo controlled design, might attenuate postprandial glucose levels in obese women. For these purposes, intramuscular microdialysis, blood sampling from arterial and venous blood of the forearm, and measurements of forearm blood flow were performed. The results showed an impaired permeability surface area for glucose (IAUC PS(glu) 31±13 vs. 124±31; p<0.05) in obese when compared with lean participants, but no differences in forearm glucose uptake appeared between the groups. Furthermore, a single dose of tadalafil 10 mg showed no improvement of the permeability surface area for glucose, glucose uptake, or circulating glucose levels in obese participants. In conclusion, the postprandial PS(glu) response was impaired in obese women showing postprandial hyperglycemia, indicating a compromised microcirculation. However, we were unable to demonstrate any acute effect on either vascular function or glucose uptake of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil.

Role of forearm vasoconstriction in the development of primary raynaud's disease

Raynaud's Disease has been characterized as arteriolar constriction with a subsequent reduction of blood flow to the fingers. Few studies have investigated the regulation of blood flow into the hand in individuals with the disease. Therefore, the purpose of this study was to determine the relationship between Raynaud's disease and the forearm blood flow (FBF) response. Ten females (20.2±1.0 years), five control (CON) and five with the disease (RAY), completed two trials: a control visit and a cold‐induced visit. During the cold‐induced trial the left hand was placed in a cold bath (12°C) to induce Raynaud's symptoms. FBF was measured using venous occlusion plethysmography (Hokanson EC6). Reactive hyperemia was then determined by occluding the forearm for five minutes at 250 mmHg followed by peak FBF measurements. FBF and mean arterial pressure (MAP) were recorded pre, during the occlusion, and post trial. RAY exhibited the typical triphasic coloration changes indicating severe ischemia. Peak FBF after the occlusion in the cold trial was greater in RAY than CON indicating greater hyperemia (28.3 ± 4.8 vs. 26.2 ± 2.2 ml/100ml/min). MAP for CON was not different from RAY (87.37 ± 1.4 vs. 87.11 ± 2.37 mmHg). RAY demonstrated the typical ischemic response in the hand in response to a cold challenge in spite of a greater reactive hyperemia in the forearm suggesting a greater vasoconstriction response between the hand and forearm.

The Selective Phosphodiesterase-5 Inhibitor Tadalafil Induces Microvascular and Metabolic Effects in Type 2 Diabetic Postmenopausal Females

The objective of the study was to explore the acute in vivo effects of the selective phosphodiesterase-5 inhibitor tadalafil on local microcirculation and regional metabolism in skeletal muscle and adipose tissue (AT). We studied eight postmenopausal female patients with type 2 diabetes (T2D) and eight nondiabetic controls (Ctrl) in the postabsorptive state and 180 min after the administration of tadalafil 10 mg. Intramuscular and sc microdialysis were combined with measurements of forearm (FBF) and AT blood flow as well as with arterial and deep venous blood sampling. Muscle capillary recruitment, as ascertained by the permeability surface area product for glucose (PS(glu)), forearm glucose uptake (FGU), interstitial lactate, and glycerol concentrations, was measured. When compared with Ctrl, T2D patients exhibited lower (P = 0.01) PS(glu) but similar FGU and FBF. After tadalafil, PS(glu) (P = 0.01) and muscle interstitial-arterial (I-A) lactate concentration gradient (P < 0.01) increased significantly in both groups, whereas FBF, FGU, and I-A glycerol remained unchanged. In AT, tadalafil did not significantly affect local blood flow, whereas the sc interstitial (I) lactate and I-A lactate concentrations increased (P < 0.01), and the I-A glycerol decreased in both groups. Finally, in multivariate analysis the PS(glu) was a strong and independent predictor of muscle glucose disposal (β: 0.737 and 0.963, P < 0.05, in Ctrl and T2D, respectively). Tadalafil emerges as an acutely acting modulator of microvascular recruitment and glucose metabolism in skeletal muscle and adipose tissue. We suggest that selective phosphodiesterase-5 blockade may provide a path forward to new therapeutics in the setting of insulin resistance.

Comparison of VOP and Doppler ultrasound in measuring forearm blood flow during direct heating

PURPOSE Venous occlusion plethysmography (VOP) is the gold standard for measuring forearm blood flow to obtain maximal skin blood flow. We sought to compare this method to Doppler ultrasound. METHODS Seven subjects (four female, three male; BMI = 23±3 kg.m−1) underwent a ramped local heating protocol. Local heating was achieved by heating the forearm with a water spray device. Doppler ultrasound of the brachial artery and forearm VOP were measured during five stages: under thermoneutral conditions (33oC), after 15 minutes of heating at 36oC, 39oC, and 42oC, and after 30 minutes of heating at 42oC. The protocol aimed to produce a linear rise in blood flow with each subsequent stage. Doppler ultrasound and VOP blood flow measurements were compared by linear regression analysis. RESULTS The protocol was successful in covering a wide range of blood flow, from normal baseline to near maximal values. Measurement of forearm blood flow using Doppler ultrasound and VOP were shown to be highly correlated, with a regression coefficient of R2 = 0.773. CONCLUSION Comparable changes in forearm blood flow can be measured using either Doppler ultrasound or VOP.

The role of the endothelium in migraine

Migraine, characterized by throbbing cephalalgia, has long been referred to as a ‘‘vascular headache’’ disorder. This stems from the putative role of the extracerebral dural and meningeal vasculature as the end organ of migraine pain, following release of inflammatory neurotransmitters from trigeminal nerve endings. Recognition of migraine as a risk factor for stroke has raised questions about the role of cerebral vessels. Associations of migraine with variant angina, Raynaud’s disorder, retinopathy, livedo reticularis and pre-eclampsia has led to speculation of systemic involvement of the vasculature, particularly the endothelium (1). Endothelial dysfunction, a precursor to atherosclerosis, is characterized by endothelial cell activation (manifested by inflammation and hypercoagulability) and vascular reactivity impairment. In the investigation of Perko et al. (2), the authors explore systemic endothelial-dependent vasodilatation in migraine patients and healthy controls. The experiments involve end-diastolic measurements of the brachial artery diameter before and after blood pressure cuff–induced hyperemia. Flow-mediated dilatation (FMD) refers to the percentage increase in diameter between the two measurements, and low values reflect impaired reactivity, a functional component of endothelial dysfunction. The authors found no differences in FMD between migraineurs and controls, nor between migraineurs with and without aura, suggesting a lack of systemic endothelial involvement. A strength of the study lies in the careful selection of the population, excluding those with hypertension, hypercholesterolemia, diabetes, abnormal body mass index (BMI) and known cardiovascular disease. Associated with vascular risk factors and predictive of vascular ischemic events, endothelial dysfunction has been referred to as ‘‘the ultimate risk of the risk factors’’ (3). Migraine, particularly with aura, has also been associated an elevated cardiovascular risk profile (4). By excluding subjects with or at risk of vascular disease, the design best allows for examination of the unconfounded migraine-endothelial function relationship. The authors go a step further by excluding those with increased carotid intima-media thickness (IMT), a structural marker of subclinical atherosclerosis. Some studies have shown a correlation between IMT and FMD (5), whereas others have not (6). If these structural and functional markers are related, exclusion of one of these markers may bias against finding differences between groups for the other. How do the findings of Perko, et al. of non-altered FMD in migraineurs fit in with the accumulating literature on this topic? As the authors summarize in their well-researched discussion, their findings concur with those of one study (7) but conflict with the results of several others (8–11). A recently published study, similarly measuring FMD and IMT in migraine, excluded persons with known risk factors for vascular disease, except for elevated BMI (12). There were no differences in FMD between migraine (with and without aura) patients and controls, except in a subgroup with transformed migraine. FMD did, however, correlate inversely with carotid IMT, which was increased in all of the migraine subgroups. This could be expected to occur if IMT was an earlier marker of disease, but wall thickening is usually found to follow rather than precede endothelial dysfunction. In light of the discrepant results from the handful of published studies, it is interesting to reflect on the findings of Napoli et al., who investigated vascular reactivity in migraine by examining both the endothelial and vascular smooth muscle cell (VSMC) components (13). They used plethysmography measurements of forearm blood flow (FBF) during brachial artery infusions of acetylcholine (Ach), an endothelium-dependent vasodilator, and nitroprusside, a vasodilator directly acting on VSMC. In addition to this they measured forearm production of NO, a reflection of endothelial activation, and cyclic guanosine monophosphate (cGMP),