Faculty Bibliography

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.

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/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.

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.

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.

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.

Although commonly encountered, patients with combined postcapillary and precapillary pulmonary hypertension (Cpc-PH) have poorly understood pulmonary vascular properties. The product of pulmonary vascular resistance and compliance, resistance-compliance (RC) time, is a measure of pulmonary vascular physiology. While RC time is lower in postcapillary PH than in precapillary PH, the RC time in Cpc-PH and the effect of pulmonary wedge pressure (PWP) on RC time are unknown. We tested the hypothesis that Cpc-PH has an RC time that resembles that in pulmonary arterial hypertension (PAH) more than that in isolated postcapillary PH (Ipc-PH). We analyzed the hemodynamics of 282 consecutive patients with PH referred for right heart catheterization (RHC) with a fluid challenge from 2004 to 2013 (cohort A) and 4,382 patients who underwent RHC between 1998 and 2014 for validation (cohort B). Baseline RC time in Cpc-PH was higher than that in Ipc-PH and lower than that in PAH in both cohorts (P < 0.001). In cohort A, RC time decreased after fluid challenge in patients with Ipc-PH but not in those with PAH or Cpc-PH (P < 0.001). In cohort B, the inverse relationship of pulmonary vascular compliance and resistance, as well as that of RC time and PWP, in Cpc-PH was similar to that in PAH and distinct from that in Ipc-PH. Our findings demonstrate that patients with Cpc-PH have pulmonary vascular physiology that resembles that of patients with PAH more than that of Ipc-PH patients. Further study is warranted to identify determinants of vascular remodeling and assess therapeutic response in this subset of PH.

BACKGROUND:Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival. METHODS:This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality. RESULTS:Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49 ng/dL (interquartile range, 1.1-4.3 ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vs liberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs 12.5 ± 10.3, P < .001) and decreased mortality (19% vs 30%, P = .03) (P value for interaction = .01). CONCLUSIONS:In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.

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 (200mg/dL), followed by L-arginine administration. Studies in 98 individuals (mean age 45.3±1.2years, 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.

Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1α protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR>60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.