Faculty Bibliography

BACKGROUND:Only half of hypertensive adults achieve blood pressure (BP) control in the United States, and it is unclear how BP control rates may be improved most effectively and efficiently at the population level. OBJECTIVE:We sought to compare the potential effects of system-wide isolated improvements in medication adherence, visit frequency, and higher physician prescription rate on achieving BP control at 52 weeks. DESIGN/METHODS:We developed a Markov microsimulation model of patient-level, physician-level, and system-level processes involved in controlling hypertension with medications. The model is informed by data from national surveys, cohort studies and trials, and was validated against two multicenter clinical trials (ALLHAT and VALUE). SUBJECTS/METHODS:We studied a simulated, nationally representative cohort of patients with diagnosed but uncontrolled hypertension with a usual source of care. INTERVENTIONS/METHODS:We simulated a base case and improvements of 10 and 50%, and an ideal scenario for three modifiable parameters: visit frequency, treatment intensification, and medication adherence. Ideal scenarios were defined as 100% for treatment intensification and adherence, and return visits occurring within 4 weeks of an elevated office systolic BP. MAIN OUTCOME/RESULTS:BP control at 52 weeks of follow-up was examined. RESULTS:Among 25,000 hypothetical adult patients with uncontrolled hypertension (systolic BP ≥ 140 mmHg), only 18% achieved BP control after 52 weeks using base-case assumptions. With 10/50%/idealized enhancements in each isolated parameter, enhanced treatment intensification achieved the greatest BP control (19/23/71%), compared with enhanced visit frequency (19/21/35%) and medication adherence (19/23/26%). When all three processes were idealized, the model predicted a BP control rate of 95% at 52 weeks. CONCLUSION/CONCLUSIONS:Substantial improvements in BP control can only be achieved through major improvements in processes of care. Healthcare systems may achieve greater success by increasing the frequency of clinical encounters and improving physicians' prescribing behavior than by attempting to improve patient adherence to medications.

BACKGROUND:Fibrosing mediastinitis (FM) is an idiosyncratic reaction to infection with Histoplasma capsulatum with a prevalence of 3:100,000 people infected. The rarity of post-histoplasmosis fibrosing mediastinitis (PHFM) in areas where H. capsulatum is endemic suggests that an abnormal immunological host response may be responsible for the development of fibrosis. Our group previously reported an association between subjects with PHFM and human leukocyte antigen (HLA)-A*02. We sought to confirm or extend those findings with application of high resolution HLA typing in a cohort of subjects with PHFM. METHODS:High-resolution HLA typing was performed on DNA samples from a new cohort 34 patients with PHFM. Control cohorts included 707 subjects from the "European American" subset of the National Marrow Donor Program(®) (NMDP) and 700 subjects from Dialysis Clinic, Inc. (DCI). The carriage frequencies of the HLA alleles identified in the PHFM, NMDP, and DCI cohorts were calculated and then all were compared. RESULTS:We found an increase in the carriage frequency of HLA-DQB1*04:02 in PHFM subjects relative to the controls (0.15 versus 0.07 in DCI and 0.05 in NMDP; p = 0.08 and 0.03). Multiple logistic regression showed that DQB1*04:02 was statistically significant (p = 0.04), while DQB1*03:02 and C*03:04 had point estimates of OR > 1, though they did not reach statistical significance. The HLA-A*02 association was not replicated. CONCLUSIONS:HLA-DQB1*04:02 is associated with PHFM, which supports the premise that an aberrant host immune response contributes to the development of PHFM.

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/RESULTS:In protocol 1, we assessed the time course of FMD and compared the repeatability of FMD using the individual maximum peak dilation (FMDpeak) and the dilation at 60 seconds (FMD60). 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 FMDpeak 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<0.001). At 2 hours, the FMDpeak 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/BACKGROUND:URL: https://clinicaltrials.gov/ Unique identifiers: NCT01334554 and NCT02126735.

BACKGROUND:Heterogeneity in response to treatment of pulmonary arterial hypertension (PAH) is a major challenge to improving outcome in this disease. Although vasodilator-responsive PAH (VR-PAH) accounts for a minority of cases, VR-PAH has a pronounced response to calcium channel blockers and better survival than vasodilator-nonresponsive PAH (VN-PAH). We hypothesized that VR-PAH has a different molecular cause from VN-PAH that can be detected in the peripheral blood. METHODS AND RESULTS/RESULTS:Microarrays of cultured lymphocytes from VR-PAH and VN-PAH patients followed at Vanderbilt University were performed with quantitative polymerase chain reaction performed on peripheral blood for the 25 most different genes. We developed a decision tree to identify VR-PAH patients on the basis of the results with validation in a second VR-PAH cohort from the University of Chicago. We found broad differences in gene expression patterns on microarray analysis including cell-cell adhesion factors and cytoskeletal and rho-GTPase genes. Thirteen of 25 genes tested in whole blood were significantly different: EPDR1, DSG2, SCD5, P2RY5, MGAT5, RHOQ, UCHL1, ZNF652, RALGPS2, TPD52, MKNL1, RAPGEF2, and PIAS1. Seven decision trees were built with the use of expression levels of 2 genes as the primary genes: DSG2, a desmosomal cadherin involved in Wnt/β-catenin signaling, and RHOQ, which encodes a cytoskeletal protein involved in insulin-mediated signaling. These trees correctly identified 5 of 5 VR-PAH patients in the validation cohort. CONCLUSIONS:VR-PAH and VN-PAH can be differentiated with the use of RNA expression patterns in peripheral blood. These differences may reflect different molecular causes of the 2 PAH phenotypes. This biomarker methodology may identify PAH patients who have a favorable treatment response.

CONTEXT/BACKGROUND: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. OBJECTIVE:The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function. DESIGN/METHODS:This was a randomized, double-blind, placebo-controlled study. SETTING/METHODS:This trial was conducted at Vanderbilt Clinical Research Center. PARTICIPANTS/METHODS:Participants included overweight individuals with prediabetes. INTERVENTIONS/METHODS: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. MAIN OUTCOME MEASURES/METHODS:The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion. RESULT/RESULTS: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. CONCLUSIONS:Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.

OBJECTIVE:Gout prevalence is high in older adults and those affected are at risk of physical disability, yet it is unclear whether they have worse physical function. METHODS:We studied gout, hyperuricemia, and physical function in 5,819 older adults (age ≥65 years) attending the 2011-2013 Atherosclerosis Risk in Communities Study visit, a prospective US population-based cohort. Differences in lower extremity function (Short Physical Performance Battery [SPPB] and 4-meter walking speed) and upper extremity function (grip strength) by gout status and by hyperuricemia prevalence were estimated in adjusted ordinal logistic regression (SPPB) and linear regression (walking speed and grip strength) models. Lower scores or times signify worse function. The prevalence of poor physical performance (first quartile) by gout and hyperuricemia was estimated using adjusted modified Poisson regression. RESULTS:Ten percent of participants reported a history of gout and 21% had hyperuricemia. There was no difference in grip strength by history of gout (P = 0.77). Participants with gout performed worse on the SPPB test; they had 0.77 times (95% confidence interval [95% CI] 0.65, 0.90, P = 0.001) the prevalence odds of a 1-unit increase in SPPB score and were 1.18 times (95% CI 1.07, 1.32, P = 0.002) more likely to have poor SPPB performance. Participants with a history of gout had slower walking speed (mean difference -0.03; 95% CI -0.05, -0.01, P < 0.001) and were 1.19 times (95% CI 1.06, 1.34, P = 0.003) more likely to have poor walking speed. Similarly, SPPB score and walking speed, but not grip strength, were worse in participants with hyperuricemia. CONCLUSION/CONCLUSIONS:Older adults with gout and hyperuricemia are more likely to have worse lower extremity, but not upper extremity, function.

BACKGROUND:Epidemiologic data for cardiac abnormality predating decreased kidney function are sparse. We investigated the associations of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) with end-stage renal disease (ESRD) risk in a community-based cohort. STUDY DESIGN/METHODS:A prospective cohort study. SETTING & PARTICIPANTS/METHODS:10,749 white and black participants at the fourth visit (1996-1998) of the Atherosclerosis Risk in Communities (ARIC) Study with follow-up through 2010. PREDICTOR/METHODS:hs-cTnT (3, 6, 9, and 14ng/L) and NT-proBNP (41.6, 81.0, 142.5, and 272.5pg/mL) levels were divided into 5 categories at the same percentiles (32th, 57th, 77th, and 91th; corresponding to ordinary thresholds of hs-cTnT), with the lowest category as a reference. OUTCOMES/RESULTS:Incident ESRD defined as initiation of dialysis therapy, transplantation, or death due to kidney disease. MEASUREMENTS/METHODS:Relative risk and risk prediction of ESRD according to hs-cTnT and NT-proBNP levels based on Cox proportional hazards models. RESULTS:During a median follow-up of 13.1 years, 235 participants developed ESRD (1.8 cases/1,000 person-years). hs-cTnT and NT-proBNP levels were associated with ESRD risk independently of each other and of potential confounders, including kidney function and albuminuria (adjusted HRs for highest category, 4.43 [95% CI, 2.43-8.09] and 2.28 [95% CI, 1.44-3.60], respectively). For hs-cTnT level, the association was significant even at the third category (HR for 6-8ng/L of hs-cTnT, 2.74 [95% CI, 1.54-4.88]). Their associations were largely consistent even among persons without decreased kidney function or history of cardiovascular disease. hs-cTnT and NT-proBNP levels both significantly improved ESRD prediction (C statistic differences of 0.0084 [95% CI, 0.0005-0.0164] and 0.0045 [95% CI, 0.0004-0.0087], respectively, from 0.884 with conventional risk factors). LIMITATIONS/CONCLUSIONS:Relatively small number of ESRD cases and single measurement of hs-cTnT and NT-proBNP. CONCLUSIONS:hs-cTnT and NT-proBNP levels independently predicted ESRD risk in the general population, with more evident results for hs-cTnT. These results suggest the involvement of cardiac abnormality, particularly cardiac injury, in the progression of reduced kidney function and/or may reflect the useful property of hs-cTnT as an end-organ damage marker.