Faculty Bibliography

DPP (dipeptidyl peptidase)-4 inhibitors are antidiabetic drugs that may increase heart failure in high-risk patients. NPY (neuropeptide Y) is coreleased with norepinephrine, causes vasoconstriction via the Y1 receptor, and is degraded by DPP4 to NPY (3-36) in vitro. NPY (3-36) decreases release of norepinephrine via the Y2 receptor. We tested the hypothesis that DPP4 inhibition would potentiate the vasoconstrictor effect of NPY. Eighteen nonsmokers (12 healthy controls and 6 with type 2 diabetes mellitus) participated in 1 of 2 randomized, double-blind, placebo-controlled crossover studies. First, subjects were randomized to order of treatment with sitagliptin 100 mg/d versus placebo for 7 days separated by 4-week washout. On the last day of treatment, NPY was infused by brachial artery and forearm blood flow was measured using plethysmography. Blood samples were collected after each dose. NPY infusions were repeated after 90-minute washout and intra-arterial enalaprilat. Second, 5 healthy subjects were randomized to crossover treatment with sitagliptin 100 mg/d plus valsartan 160 mg/d versus placebo plus valsartan. NPY infusions were performed on the seventh day of treatment. NPY caused dose-dependent vasoconstriction. During enalaprilat, sitagliptin significantly potentiated NPY-induced vasoconstriction in controls and diabetics ( P≤0.02 for forearm blood flow in either group). Baseline norepinephrine release was increased during sitagliptin and enalaprilat, but not further by NPY. Sitagliptin increased the ratio of NPY to NPY (3-36). During valsartan, sitagliptin also significantly potentiated NPY-induced vasoconstriction ( P=0.009 for forearm blood flow). Potentiation of endogenous NPY could contribute to cardiovascular effects of DPP4 inhibitors in patients taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg^-1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

In a physical activity study, the 7-day physical activity log viewed as an alloyed gold standard was used to correct the measurement error in the physical activity questionnaire. Due to correlations between the errors in the two measurements, the usual regression calibration may result to a biased estimate of the calibration factor. We propose a method of removing the correlation through orthogonal decomposition of the errors, then the usual regression calibration can be applied. Simulation studies show that our method can effectively correct the bias.

AIMS/HYPOTHESIS:Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. METHODS:mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. RESULTS:vessels (maximal response 39.3 ± 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants. CONCLUSIONS/INTERPRETATION:CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.

BACKGROUND: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: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:receptor antagonist in ACE inhibitor-associated angioedema.

Microarray studies generate a large number of p-values from many gene expression comparisons. The estimate of the proportion of the p-values sampled from the null hypothesis draws broad interest. The two-component mixture model is often used to estimate this proportion. If the data are generated under the null hypothesis, the p-values follow the uniform distribution. What is the distribution of p-values when data are sampled from the alternative hypothesis? The distribution is derived for the chi-squared test. Then this distribution is used to estimate the proportion of p-values sampled from the null hypothesis in a parametric framework. Simulation studies are conducted to evaluate its performance in comparison with five recent methods. Even in scenarios with clusters of correlated p-values and a multicomponent mixture or a continuous mixture in the alternative, the new method performs robustly. The methods are demonstrated through an analysis of a real microarray dataset.

Background/UNASSIGNED:Respiratory syncytial virus (RSV) and human rhinovirus (HRV) are the most common viruses associated with acute respiratory tract infections in infancy. Viral interference is important in understanding respiratory viral circulation and the impact of vaccines. Methods/UNASSIGNED:To study viral interference, we evaluated cases of RSV and HRV codetection by polymerase chain reaction in 2 prospective birth cohort studies (the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure [INSPIRE] study and the Tennessee Children's Respiratory Initiative [TCRI]) and a double-blinded, randomized, controlled trial (MAKI), using adjusted multivariable regression analyses. Results/UNASSIGNED:Among 3263 respiratory tract samples, 24.5% (798) and 37.3% (1216) were RSV and HRV positive, respectively. The odds of HRV infection were significantly lower in RSV-infected infants in all cohorts, with adjusted odds ratios of 0.30 (95% confidence interval [CI], .22-.40 in the INSPIRE study, 0.18 (95% CI, .11-.28) in the TCRI (adjusted for disease severity), and 0.34 (95% CI, .16-.72) in the MAKI trial. HRV infection was significantly more common among infants administered RSV immunoprophylaxis, compared with infants who did not receive immunoprophylaxis (OR, 1.65; 95% CI, 1.65-2.39). Conclusions/UNASSIGNED:A negative association of RSV on HRV codetection was consistently observed across populations, seasons, disease severity, and geographical regions. Suppressing RSV infection by RSV immunoprophylaxis might increase the risk of having HRV infection.

Twenty to thirty percent of patients undergoing cardiac surgery develop acute kidney injury (AKI). In mice, inhibition of soluble epoxide hydrolase (sEH) attenuates renal injury following ischemia-reperfusion. We tested the hypothesis that functional variants of EPHX2, encoding sEH, are associated with AKI after cardiac surgery. We genotyped patients in two independent cardiac surgery cohorts for functional EPHX2 polymorphisms, Lys55Arg and Arg287Gln, and determined AKI using Acute Kidney Injury Network criteria. The 287Gln variant was not associated with AKI. In the discovery cohort, the gain-of-function 55Arg variant was associated with an increased incidence of AKI in univariate (p = 0.03) and multivariable (p = 0.04) analyses. In white patients without chronic kidney disease (CKD), the 55Arg variant was independently associated with AKI with an OR of 2.04 (95% CI 0.95-4.42) for 55Arg heterozygotes and 31.53 (1.57-633.19) for homozygotes (p = 0.02), after controlling for age, sex, body mass index, baseline estimated glomerular filtration rate, and use of cardiopulmonary bypass. These findings were replicated in the second cardiac surgery cohort. 12,13- and total- dihydroxyoctadecanoic acids (DiHOME): epoxyoctadecanoic acids (EpOME) ratios were increased in EPHX2 55Arg variant carriers, consistent with increased hydrolase activity. The EPHX2 Lys55Arg polymorphism is associated with AKI following cardiac surgery in patients without preexisting CKD. Pharmacological strategies to decrease sEH activity might decrease postoperative AKI.

For many continuous distributions, a closed-form expression for their quantiles does not exist. Numerical approximations for their quantiles are developed on a distribution-by-distribution basis. This work develops a general approximation for quantiles using the Taylor expansion. Our method only requires that the distribution has a continuous probability density function and its derivatives can be derived to a certain order (usually 3 or 4). We demonstrate our unified approach by approximating the quantiles of the normal, exponential, and chi-square distributions. The approximation works well for these distributions.