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Background: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. Methods: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. Results: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. Conclusions: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.

Objective Metabolic syndrome is associated with insulin resistance and increased future risk of type 2 diabetes. This study investigates the relationship between insulin secretion, insulin resistance and individual metabolic syndrome components in subjects without a prior diagnosis of diabetes. Research Design and Methods We assessed insulin secretion during hyperglycemic clamps by infusing dextrose to maintain hyperglycemia (200 mg/dL), followed by L-arginine administration. Studies in 98 individuals (mean age 45.3 ± 1.2 years, 56% female, 22% African-American, 49% with metabolic syndrome) were analyzed. We tested the association between the number of metabolic syndrome components and individual outcome variables using linear mixed-effects models to adjust for potential confounding effects of age, sex, and race. Results Insulin sensitivity index was reduced in the presence of 1 or more metabolic syndrome components. Insulin sensitivity was independently associated with age, waist circumference, male gender and decreased HDL cholesterol. The acute insulin response was greater with two or more metabolic syndrome components, and late glucose-stimulated and L-arginine-stimulated insulin responses exhibited a similar trend. In contrast, the disposition index, a measure of beta cell compensation for insulin resistance, was linearly lower with the number of metabolic syndrome components, and was negatively associated with age, Caucasian race, waist circumference, fasting glucose, and decreased HDL cholesterol. Conclusions The insulin secretory response in metabolic syndrome is inadequate for the worsening insulin sensitivity, as demonstrated by a decline in disposition index. A dysfunctional insulin secretory response is evident in non-diabetic individuals and worsens with accumulation of metabolic syndrome components.

Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance.The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function.This was a randomized, double-blind, placebo-controlled study.This trial was conducted at Vanderbilt Clinical Research Center.Participants included overweight individuals with prediabetes.Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment.The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion.Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per μU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per μU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P.30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 μg/mg Cr. This effect persisted 3 months after sildenafil discontinuation.Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.

Acromegaly is usually due to the excessive secretion of GH by a pituitary adenoma. It is frequently accompanied by comorbidities that compromise quality of life and results in elevated mortality rates.To evaluate mortality and morbidity in patients with acromegaly receiving multimodal care.Tertiary care center.Retrospective evaluation of 442 patients (65.4% women; mean age, 43.5 ± 13.1 y) followed for a median of 6 years (interquartile range [IQR], 3-10).Twenty-two patients died during the study period (4.9%), representing a total standardized mortality ratio (SMR) of 0.72 (95% confidence interval [CI], 0.41-1.03). Standardized mortality ratios were 1.5 and 0.44 for patients whose last GH was above and below 2.5 ng/mL, respectively; 1.17 and 0.16 for those whose last GH was above and below 1 ng/mL, respectively; and 0.94 and 0.46 for those whose last IGF-1 was above and below 1.2 times the upper limit of normal (ULN), respectively. The prevalence of diabetes mellitus, hypertension, heart disease, and cancer was 30%, 35%, 8%, and 4.7%, respectively. The most common cause of death was cancer. On multivariate analysis, diabetes, heart disease, and cancer were related to a baseline GH10 ng/mL; the presence of cancer and the last IGF-1 were significant predictors of mortality. Survival decreased as the latest GH levels increased from1 ng/mL to5 ng/mL and as IGF-1 increased from1.2 to2 times the ULN.Mortality in acromegaly can be successfully reduced, provided patients are treated using a multimodal approach with careful management of comorbidities.

Background The B 2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema in 1 study of European patients. Objective We sought to test the hypothesis that a bradykinin B 2 receptor antagonist would shorten time-to-resolution from ACE inhibitor-associated angioedema. Methods Patients with ACE inhibitor–associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge. Results Thirty-three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two-thirds of patients were black and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups ( P = .19 for the primary symptom and P > .16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time-to-resolution of symptoms was similar in black and white patients. Conclusions This study does not support clinical efficacy of a bradykinin B 2 receptor antagonist in ACE inhibitor-associated angioedema.

The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of ACE inhibitor-associated angioedema in one study of European patients. Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were randomized within six hours of presentation to SQ icatibant 30 mg or placebo at zero and six hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge. Thirty-one patients were randomized to and received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded. Two-thirds of patients were African American and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups [p=0.19 for the primary symptom (Figure) and p>0.16 for individual symptoms of face, lip, tongue, or eyelid swelling]. Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the two treatment groups. Lip swelling was more severe in blacks (p=0.03), while tongue swelling was more severe in whites (0.02). White patients were significantly more likely to receive epinephrine (p=0.01). Time-to-resolution of symptoms was similar in blacks and whites. This study does not support the clinical efficacy of administration of a B 2 receptor blocker in black or white American patients with ACE inhibitor-associated angioedema.

Context: The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction. Objective: To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil. Design: IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2). Setting: Two-center study. Participants: Obese AA women. Intervention: A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks. Main outcome: IS, FMD. Results: G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], −0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, −0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, −2.6 (95% CI, −5.1 to −0.1; P = .04). Conclusions: The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.

A goal of aspirin therapy is to inhibit thromboxane production and platelet aggregation without inhibiting endothelial production of the vasodilator and anti‐thrombotic prostacyclin. This study tested the hypothesis that extended‐release aspirin (NHP‐554C) would have increased selectivity for inhibition of basal and simulated thromboxane formation compared to immediate‐release aspirin (ASA). Thirty‐six healthy subjects were randomized to NHP‐554C or ASA groups. Within each group, subjects were randomized to 5‐day treatment with 81 mg/d, 162.5 mg/d and placebo in a crossover design in which treatment periods were separated by 2‐week washout. On the fifth day of treatment, 81 mg/d and 162.5 mg/d ASA reduced basal urinary excretion of the stable thromboxane metabolite 11‐dehydro‐thromboxane B2 62.3% and 66.2% and basal excretion of the stable prostacyclin metabolite 2,3‐dinor‐6‐keto‐PGF1α 22.8% and 26.5%, respectively, compared to placebo. NHP‐554C 81 mg/d and 162.5 mg/d reduced 11‐dehydro‐thromboxane B2 53% (P = 0.03 vs. ASA 81 mg/d) and 67.9% and 2,3‐dinor‐6‐keto‐PGF1α 13.4% and 18.5%, respectively. NHP‐554C 81 mg/d did not significantly reduce basal excretion of the prostacyclin metabolite. Both doses of ASA and NHP significantly reduced excretion of both thromboxane and prostacyclin metabolites following intravenous bradykinin. During NHP‐554C 162.5 mg/d, but not during ASA, bradykinin significantly increased urinary 2,3‐dinor‐6‐keto‐PGF1α. Nevertheless, 11‐dehydro‐thromboxane B2 and 2,3‐dinor‐6‐keto‐PGF1α responses to bradykinin were statistically similar during ASA and NHP‐554C. In conclusion, at doses of 81 and 162.5 mg/d immediate‐ and extended‐release aspirin selectively decrease basal thromboxane production. Both forms of aspirin decrease bradykinin‐stimulated thromboxane and prostacyclin production, but some stimulated prostacyclin production remains during treatment with NHP‐554C.

Background Flow‐mediated dilation ( FMD ) is used to assess endothelial function through changes in vascular diameter after hyperemia. High‐fat meal ( HFM ) has been shown to induce endothelial dysfunction; recent studies, however, reported conflicting results in obese African American women ( AAW ). Differences in the method used to analyze FMD may explain these discrepancies. Methods and Results In protocol 1, we assessed the time course of FMD and compared the repeatability of FMD using the individual maximum peak dilation ( FMD peak ) and the dilation at 60 seconds ( FMD 60 ). Sixteen AAW (age, 42±10.4 years; body mass index [ BMI], 39±5.8 kg/m 2 ) were studied on 2 occasions, 4 weeks apart, under fasting conditions (study 1 and study 2). In protocol 2, we used the most repeatable measurement from protocol 1 to assess changes in endothelial function after an HFM in 17 AAW (agen 42±11.1 years; BMIn 38±5.6 kg/m 2 ). We found that FMD peak was the most repeatable measurement (N=16; study 1, 5.31±3.12% and study 2, 5.80±2.91%; r =0.94). After an HFM , the baseline brachial artery diameter significantly increased at 2 hours (0.10 mm; 95% confidence interval [ CI ], 0.01–0.18; P =0.03) and at 4 hours (0.17 mm; 95% CI , 0.09–0.25; P FMD peak decreased compared with pre‐ HFM (−1.76; 95% CI , −3.55–0.02; P≤ 0.05). Conclusions The individual's maximum peak dilation after hyperemia is the most consistent measure to assess the effect of an HFM on endothelial function. Endothelial dysfunction occurred at 2 hours after an HFM in AAW . Clinical Trial Registration URL : https://clinicaltrials.gov/ Unique identifiers: NCT 01334554 and NCT 02126735.

Parkinson disease, an α-synucleinopathy, is associated with reduced insulin sensitivity, impaired glucose tolerance, and diabetes mellitus. Importantly, these metabolic alterations have been shown to contribute to disease progression. The purpose of this study was to determine if reduced insulin sensitivity is also present in other α-synucleinopathies associated with autonomic failure. We studied 19 patients with multiple system atrophy and 26 patients with pure autonomic failure. For comparison, we studied 8 healthy controls matched for body mass index. Insulin sensitivity and beta cell function were calculated using fasting glucose and insulin levels according to the homeostatic model assessment 2. A multiple linear regression model was performed to determine factors that predict insulin sensitivity in autonomic failure. There was a significant difference in insulin sensitivity among groups (P = 0.048). This difference was due to lower insulin sensitivity in multiple system atrophy patients: 64 % [interquartile range (IQR), 43 to 117] compared to healthy controls 139 % (IQR, 83 to 212), P = 0.032. The main factor that contributed to the reduced insulin sensitivity was the presence of supine hypertension and residual sympathetic tone. Multiple system atrophy patients have reduced insulin sensitivity that is associated with residual sympathetic activation and supine hypertension. These patients may therefore be at high risk for development of impaired glucose tolerance and diabetes mellitus.

CD36, a scavenger receptor expressed on endothelial cells, interacts with thrombospodin-1, a matrix protein that modulates nitric oxide-soluble guanylate cyclase (NO-sGC) signaling. CD36 genetic variants associate with endothelial dysfunction, atherosclerosis, hypertension and insulin resistance. A coding variant of CD36 (rs3211938, G/T genotype) that causes partial CD36 deficiency (50% reduction) is common (~18%) in African Americans (AA); however, it is unknown, if this genotype influences NO-dependent endothelial function. This study examined whether potentiating NO-sGC pathways with the phosphodiesterase 5 inhibitor, sildenafil citrate, improves endothelial function and insulin sensitivity in AA women with or without the G/T genotype. Forty-six AA women with metabolic syndrome (MetS) participated in a 4-week, parallel-arm, double-blind, and placebo-controlled study. Carefully matched subjects were randomly assigned to sildenafil citrate 20 mg TID versus placebo; sildenafil (n= 23, 42±10 years old, BMI 39±5 kg/m2, fasting insulin 15±8 uU/ml) and placebo (n=23, age 43±10, BMI 39±6 kg/m2, fasting insulin 14±10 uU/ml). Primary endpoints were insulin sensitivity and endothelial function measured by intravenous glucose tolerance test and flow mediated dilation, respectively. Treatment compliance was documented with plasma sildenafil levels (mean 57±50 ng/ml). There was no difference in insulin sensitivity (p=0.676) or flow-mediated dilation (p=0.649) between intervention groups. However, subgroup analyses showed a significant interaction between sildenafil citrate treatment and G/T genotype (p=0.018). Sildenafil citrate improved endothelial function in G/T carriers (the mean difference: 2.9, the 95% CI: -0.90 to 6.8, p = 0.126) and decreased endothelial function in T/T carriers (the mean difference: -2.6, the 95% CI: -5.1 to -0.1, p = 0.040). We conclude that the rs3211938 common CD36 genetic variant influences NO-dependent endothelial function in response to chronic treatment with phosphodiesterase 5 inhibition. Further studies are needed to determine if rs3211938 and other common CD36 genotypes influence endothelial function and the inter-individual variability in response to the drug.

The clinical presentation of autonomic failure is orthostatic hypotension. Severely affected patients require pharmacological treatment to prevent presyncopal symptoms or frank syncope. We previously reported in a proof of concept study that pediatric doses of the norepinephrine transporter blockade, atomoxetine, increases blood pressure in autonomic failure patients with residual sympathetic activity compared with placebo. Given that the sympathetic nervous system is maximally activated in the upright position, we hypothesized that atomoxetine would be superior to midodrine, a direct vasoconstrictor, in improving upright blood pressure and orthostatic hypotension–related symptoms. To test this hypothesis, we compared the effect of acute atomoxetine versus midodrine on upright systolic blood pressure and orthostatic symptom scores in 65 patients with severe autonomic failure. There were no differences in seated systolic blood pressure (means difference=0.3 mm Hg; 95% confidence [CI], −7.3 to 7.9; P =0.94). In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P =0.03) compared with midodrine. Furthermore, atomoxetine (means difference=0.4; 95% CI, 0.1 to 0.8; P =0.02), but not midodrine (means difference=0.5; 95% CI, −0.1 to 1.0; P =0.08), improved orthostatic hypotension–related symptoms as compared with placebo. The results of our study suggest that atomoxetine could be a superior therapeutic option than midodrine for the treatment of orthostatic hypotension in autonomic failure.

Chronic administration of the PDE5 inhibitor sildenafil citrate improves insulin sensitivity in high fat-fed mice. A small study in patients with metabolic syndrome found that one-month treatment with tadalafil with or without ACE inhibition improves disposition index (DI) and β-cell function, as measured by IVGTT. We report the results of a randomized, double-blind, placebo-controlled study of the effect of 3-month treatment with sildenafil (25mg t.i.d.) on insulin sensitivity and secretion assessed using hyperglycemic clamps in individuals with impaired fasting glucose and/or impaired glucose tolerance. Among 51 subjects randomized, 21 subjects completed sildenafil treatment [8 men, 2 black Americans, body mass index (BMI) 35.7±6.8 Kg/m 2 ], and 21 completed placebo treatment (8 men, 6 black Americans, BMI 36.4±6.6 Kg/m 2 ). There was no significant difference in acute- or late-phase glucose-stimulated insulin secretion (GSIS) between groups. In contrast, insulin sensitivity index (ISI) and DI were significantly higher in the sildenafil group ( Figure , adjusted means and 95% CI after controlling for baseline measurements and BMI, *P

Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p = 0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p = 0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p = 0.022). Plasma EETs correlated with insulin sensitivity index (r = 0.64, p = 0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.

Severely affected patients with autonomic failure require pressor agents to counteract the blood pressure fall and improve presyncopal symptoms upon standing. Previous studies suggest that combination ergotamine and caffeine may be effective in the treatment of autonomic failure, but the efficacy of this drug has not been evaluated in controlled trials. Therefore, we compared the effects of ergotamine/caffeine on seated blood pressure and orthostatic tolerance and symptoms in 12 primary autonomic failure patients without history of coronary artery disease. Patients were randomized to receive a single oral dose of placebo, midodrine (5-10 mg), or ergotamine and caffeine (1 mg and 100 mg, respectively) in a single-blind, crossover study. Blood pressure was measured while patients were seated and after standing for up to 10 minutes, at baseline and at 1 hour post-drug. Ergotamine/caffeine increased seated systolic blood pressure, the primary outcome, compared with placebo (131±19 and 95±12 mmHg, respectively, at 1 hour post-drug; p=0.003 for time effect). Midodrine also significantly increased seated systolic blood pressure (121±19 mmHg at 1 hour post-drug; p=0.015 for time effect versus placebo), but this effect was not different from ergotamine/caffeine (p=0.621). There was no significant effect of either medication on orthostatic tolerance; however, ergotamine/caffeine improved presyncopal symptoms (p=0.034). These findings suggest that combination ergotamine and caffeine elicits a seated pressor response that is similar in magnitude to midodrine, and improves symptoms in autonomic failure. Thus, ergotamine/caffeine could be used as an alternate treatment for autonomic failure, in carefully selected patients without comorbid coronary artery disease.

Obesity has a greater detrimental impact on the health of African American (AA) women than any other racial or gender group. Nearly 80% of AA women are overweight or obese and have higher incidence of insulin resistance compared to Caucasian women. The sympathetic nervous system (SNS) is increased in obesity and previous studies have reported that it may contribute to insulin resistance. However, most of these studies were performed in Caucasians. Thus, the contribution of the SNS to insulin resistance in African Americans remains unknown.The aim of this study was to determine if sympathetic activity is increased in obese AA women with insulin resistance. A total of 35 obese AA women with metabolic syndrome were studied (age 43±9 years, body mass index 38.7±5.5 Kg/m 2 , percentage body fat 48±4). Insulin sensitivity (SI) was evaluated by frequently sampled intravenous tolerance test and analyzed with Bergman's minimal model (MINMOD). Measurement of sympathetic regulation of vasomotor tone and baroreflex gain were determined with baroreflex-cross spectral analysis. Our results showed that SI was directly associated with baroreflex sensitivity, Figure. Subjects with insulin resistance (SISBP ; 5.9±3.4 vs 3.7±2.0 mm Hg 2 , P=0.057). In conclusion, insulin resistance is associated with decreased baroreflex gain and increased sympathetic activity in obese AA women.

Flow mediated dilation (FMD) is a noninvasive technique to assess endothelial function in humans. In most studies FMD is reported as the percent change in brachial artery diameter at 60 seconds after cuff deflation relative to baseline (%FMD at 60 seconds). Recently the availability of automated computer-based edge detection allows measurement of peak dilation during the entire time course of brachial dilation post-hyperemia. Considering that changes in arterial diameter in response to shear stress is a continuous process and that peak dilation may differ in pathological states and occur at any arbitrary time point, we examined the time course of brachial artery FMD after a 5-min period of ischemia in 38 obese African American women (42±9.3 years old, BMI 39±6, % body fat 48.2±4.3, SBP 131±13, DBP 83±8 mm Hg, HR 77±12 bpm). Results were analyzed using brachial analyzer software (Medical Imaging Applications LLC). Baseline brachial artery diameter was 3.95±0.55 mm, the time to peak was 48.93 ±13.82 seconds. The percent change in FMD (%FMD) obtained at peak diameter was greater (4.7±3.19 mm) than %FMD at 60 seconds (3.23±4.33 mm); mean difference = 1.4 (95% CI, 0.54-2.4, P=0.003). A large proportion (79%) of true peak diameters fell outside the 60 seconds time frame typically used to assess FMD, Figure. Our results suggest that the peak vasodilator effect occurs before 60±5 seconds in the majority of our population. Therefore, the evaluation of FMD as a continuous measurement has greater accuracy and less variability for the evaluation of FMD compared with an arbitrary time point.

Epoxyeicosatrienoic acids (EETs) induce vasodilation via activation of calcium-sensitive potassium channels and smooth muscle cell hyperpolarization. Soluble epoxide hydrolase (sEH) hydrolyzes EETs to less biologically active metabolites. The variant Gln287 of EPHX2 encodes for a sEH enzyme with reduced hydrolase activity. In murine models of type 2 diabetes, inhibition of sEH or EPHX2 deletion results in improved insulin sensitivity. In humans, forearm blood flow is significantly increased in Gln287 variant allele carriers. Given that insulin sensitivity is influenced by vascular perfusion, we hypothesized that insulin sensitivity would be increased in Gln287-carriers compared with wild-type individuals. Insulin secretion and sensitivity were assessed in 63 volunteers (43 with metabolic syndrome, 34 females, 42.5 ± 13 years old, 15 black Americans) during hyperglycemic clamps. Statistical analyses were adjusted for BMI. Plasma total- (r=0.63, p=0.007), 14-15- (r=0.62, p=0.008), and 11-12- (r=0.57, p=0.02) EET concentrations correlated with insulin sensitivity. There was no effect of genotype on insulin secretion (not shown). In individuals without metabolic syndrome, insulin sensitivity was significantly increased in Gln287 variant carriers compared with wild-type individuals (Fig. A). Insulin sensitivity was decreased in individuals with the metabolic syndrome, but also trended higher in Gln287 variant carriers when compared with wild-type individuals (Fig. B). Taken together, these results suggest that the loss-of-function Gln287 variant of EPHX2 is associated with increased insulin sensitivity.

Orthostatic hypotension is the most disabling symptom of autonomic failure. Severely affected patients often require medication to counteract the blood pressure fall and to improve pre-syncopal symptoms on standing. Isolated clinical observations have suggested that the combination ergotamine and caffeine can be useful in the treatment of orthostatic hypotension. The aim of this study was to examine the effect of the combination ergotamine and caffeine on blood pressure and pre-syncopal symptoms on standing in a group of patients with autonomic failure. A total of 12 patients participated in this study. Eight were men and the average age was 64±10 years. The combination ergotamine and caffeine increased seated SBP by 19 mm Hg compared with placebo (95% CI: -2 to 40 mm Hg, P=0.07) (Figure A) and reduced the orthostatic symptom score by 9 points (95% CI: 0.9 to 16, P=0.03), compared with baseline (Figure B). In conclusion, the combination ergotamine and caffeine could be an alternative therapy for orthostatic hypotension in patients with autonomic failure.