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1.  Fasting 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography to Detect Metabolic Changes in Pulmonary Arterial Hypertension Hearts over 1 Year 
Background: The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34+CD133+) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function.
Methods: Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34+CD133+ cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation.
Measurements and Results: FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34+CD133+ cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving β-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34+CD133+ cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts.
Conclusions: PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.
doi:10.1513/AnnalsATS.201206-029OC
PMCID: PMC3960991  PMID: 23509326
hypoxia-inducible factor 1; alpha subunit; positron emission tomography; fluorodeoxyglucose F18; right ventricle; heart failure
2.  Biomarkers in Asthma: A Real Hope to Better Manage Asthma 
Clinics in chest medicine  2012;33(3):459-471.
SYNOPSIS
Diagnosis and treatment of asthma are currently based on assessment of patient symptoms and physiologic tests of airway reactivity. The morbidities and costs associated with the over and/or under treatment of this common disease, as well as the growing numbers of biologically-specific targeted strategies for therapy, provide a rationale for development of biomarkers to evaluate the presence and type of inflammation in individuals with asthma in order to optimize treatment plans. Research over the past decade has identified an array of biochemical and cellular biomarkers, which reflect the heterogeneous and multiple mechanistic pathways that may lead to asthma. These mechanistic biomarkers offer hope for optimal design of therapies targeting the specific pathways that lead to inflammation. This article provides an overview of blood, urine and airway biomarkers, summarizes the pathologic pathways that they signify, and begins to describe the utility of biomarkers in the future care of patients with asthma.
doi:10.1016/j.ccm.2012.06.007
PMCID: PMC3494969  PMID: 22929095
asthma; biomarkers; asthma management
3.  IL6R Variation Asp358Ala Is a Potential Modifier of Lung Function in Asthma 
Background
The IL6R SNP rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r2=1) with the IL6R coding SNP rs2228145 (Asp358Ala). This IL6R coding change increases IL6 receptor shedding and promotes IL6 transsignaling.
Objectives
To evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes.
Methods
The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL6 receptor (sIL6R) levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL6R protein expression in BAL cells and endobronchial biopsies.
Results
The minor C allele of IL6R SNP rs2228145 was associated with lower ppFEV1 in the SARP cohort (p=0.005), the CSGA cohort (0.008), and in combined cohort analysis (p=0.003). Additional associations with ppFVC, FEV1/FVC, and PC20 were observed. The rs2228145 C allele (Ala358) was more frequent in severe asthma phenotypic clusters. Elevated serum sIL6R was associated with lower ppFEV1 (p=0.02) and lower ppFVC (p=0.008) (N=146). IL6R protein expression was observed in BAL macrophages, airway epithelium, vascular endothelium, and airway smooth muscle.
Conclusions
The IL6R coding SNP rs2228145 (Asp358Ala) is a potential modifier of lung function in asthma and may identify subjects at risk for more severe asthma. IL6 transsignaling may have a pathogenic role in the lung.
doi:10.1016/j.jaci.2012.03.018
PMCID: PMC3409329  PMID: 22554704
soluble interleukin 6 receptor; sIL6R; interleukin 6; IL6; asthma; pulmonary lung function; severe asthma; IL6 transsignaling; genetic variation; SNP rs2228145
4.  High Levels of Zinc-Protoporphyrin Identify Iron Metabolic Abnormalities in Pulmonary Arterial Hypertension 
Iron homeostasis influences the development of pulmonary arterial hypertension (PAH) associated with hypoxia or hematologic disorders. To investigate whether severity of idiopathic PAH (IPAH) is impacted by alterations in iron metabolism, we assessed iron metabolic markers, including levels of Zinc-protoporphyrin (Zn-pp), transferrin receptor, and red blood cell numbers and morphology in IPAH, associated PAH (APAH) and sleep apnea induced pulmonary hypertension (PH) patients in comparison to healthy controls and asthmatics. Despite similarly normal measures of iron metabolism, Zn-pp levels in IPAH and sleep apnea patients were elevated ~2-fold, indicating deficient iron incorporation to form heme and levels were closely related to measures of disease severity. Consistent with high Zn-PP, PAH patients had increased red cell distribution width (RDW). In an expanded cohort including patients with IPAH and familial disease (FPAH) the RDW was validated and related to clinical parameters of severity, including pulmonary artery pressures and 6 minute walk distances. These results reveal an increased prevalence of subclinical functional iron deficiency in primary forms of PAH that is quantitatively related to disease severity. This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients.
doi:10.1111/j.1752-8062.2011.00301.x
PMCID: PMC3575639  PMID: 21884511
5.  Safety of Investigative Bronchoscopy in the Severe Asthma Research Program 
Background
Investigative bronchoscopy was performed in a subset of participants in the Severe Asthma Research Program (SARP) to gain insights into the pathobiology of severe disease. We evaluated the safety aspects of this procedure in this cohort with specific focus on patients with severe asthma.
Objective
To prospectively evaluate changes in lung function and the frequency of adverse events related to investigative bronchoscopy.
Methods
Bronchoscopy was performed using a common Manual of Procedures. A subset of very severe asthma was defined by severe airflow obstruction, chronic oral corticosteroid use and recent asthma exacerbations. Subjects were monitored for changes in lung function and contacted by telephone for 3 days after the procedure.
Results
436 subjects underwent bronchoscopy (97 normal, 196 not severe, 102 severe and 41 very severe asthma). Nine subjects were evaluated in hospital settings after bronchoscopy; seven of these were respiratory related events. Recent Emergency Department visits, chronic oral corticosteroid use and a history of pneumonia were more frequent in subjects who had asthma exacerbations after bronchoscopy. The fall in FEV1 following bronchoscopy was similar in the severe compared to milder asthma group. Pre-bronchodilator FEV1 was the strongest predictor of change in FEV1 after bronchoscopy with larger decreases observed in subjects with better lung function.
Conclusions
Bronchoscopy in severe asthma subjects was well tolerated. Asthma exacerbations were rare and reduction in pulmonary function after the procedure was similar to subjects with less severe asthma. With proper precautions, investigative bronchoscopy can be performed safely in severe asthma.
doi:10.1016/j.jaci.2011.02.042
PMCID: PMC3149754  PMID: 21496892
investigative bronchoscopy; safety; severe asthma; exacerbation
6.  Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma 
Rationale: Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FeNO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FeNO levels would identify a more reactive, at-risk asthma phenotype.
Methods: FeNO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program.
Measurements and Main Results: FeNO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FeNO levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FeNO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FeNO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care.
Conclusions: Grouping of asthma by FeNO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.
doi:10.1164/rccm.200905-0695OC
PMCID: PMC2874447  PMID: 20133930
nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath
7.  Pulmonary Gas Transfer Related to Markers of Angiogenesis during the Menstrual Cycle 
Gas transfer in the female lung varies over the menstrual cycle in parallel with the cyclic angiogenesis that occurs in the uterine endometrium. Given that vessels form and regress in the uterus under the control of hormones, angiogenic factors and pro-angiogenic circulating bone marrow-derived progenitor cells, we tested the possibility that variation in pulmonary gas transfer over the menstrual cycle is related to a systemic cyclic pro-angiogenic state that influences lung vascularity. Women were evaluated over the menstrual cycle with weekly measures of lung diffusing capacity and its components, the pulmonary vascular capillary bed and membrane diffusing capacity, and their relation to circulating CD34+CD133+ progenitor cells, hemoglobin, factors affecting hemoglobin binding affinity, and pro-angiogenic factors. Lung diffusing capacity varied over the menstrual cycle, reaching a nadir during the follicular phase following menses. The decline in lung diffusing capacity was accounted for by ~25% decrease in pulmonary capillary blood volume. In parallel, circulating CD34+CD133+ progenitor cells decreased by ~24%, and were directly related to angiogenic factors, and to lung diffusing capacity and pulmonary capillary blood volume. The finding of greater number of lung microvessels in ovariectomized female mice receiving estrogen as compared to placebo verified that pulmonary vascularity is influenced by hormonal changes. These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle.
doi:10.1152/japplphysiol.00614.2007
PMCID: PMC3038173  PMID: 17717117
Gas transfer; endothelial progenitor cell; angiogenesis; menstrual cycle
8.  Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program 
Background
Severe asthma causes the majority of asthma morbidity. Understanding mechanisms that contribute to the development of severe disease is important.
Objective
The goal of the Severe Asthma Research Program is to identify and characterize subjects with severe asthma to understand pathophysiologic mechanisms in severe asthma.
Methods
We performed a comprehensive phenotypic characterization (questionnaires, atopy and pulmonary function testing, phlebotomy, exhaled nitric oxide) in subjects with severe and not severe asthma.
Results
A total of 438 subjects with asthma were studied (204 severe, 70 moderate, 164 mild). Severe subjects with asthma were older with longer disease duration (P < .0001), more daily symptoms, intense urgent health care utilization, sinusitis, and pneumonia (P ≤ .0001). Lung function was lower in severe asthma with marked bronchodilator reversibility (P < .001). The severe group had less atopy by skin tests (P = .0007), but blood eosinophils, IgE, and exhaled nitric oxide levels did not differentiate disease severity. A reduced FEV1, history of pneumonia, and fewer positive skin tests were risk factors for severe disease. Early disease onset (age < 12 years) in severe asthma was associated with longer disease duration (P < .0001) and more urgent health care, especially intensive care (P = .002). Later disease onset (age ≥ 12 years) was associated with lower lung function and sinopulmonary infections (P ≤ .02).
Conclusion
Severe asthma is characterized by abnormal lung function that is responsive to bronchodilators, a history of sinopulmonary infections, persistent symptoms, and increased health care utilization.
Clinical implications
Lung function abnormalities in severe asthma are reversible in most patients, and pneumonia is a risk factor for the development of severe disease.
doi:10.1016/j.jaci.2006.11.639
PMCID: PMC2837934  PMID: 17291857
Severe asthma; definition; bronchodilator response; pathophysiology; phenotype; pneumonia
9.  Alterations of the Arginine Metabolome in Asthma 
Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation.
Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity.
Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FeNO), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated.
Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FeNO and serum arginase activity. However, Arg bioavailability was positively associated with FeNO only in healthy control subjects; Arg bioavailability was unrelated to FeNO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma.
Conclusions: Unlike FeNO, Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.
doi:10.1164/rccm.200710-1542OC
PMCID: PMC2556449  PMID: 18635886
asthma; arginine; arginase; nitric oxide; methylarginine
10.  Gene Expression Profile of Human Airway Epithelium Induced by Hyperoxia In Vivo 
Hyperoxia leads to oxidative modification and damage of macromolecules in the respiratory tract with loss of biological functions. Given the lack of antioxidant gene induction with acute exposure to 100% oxygen, we hypothesized that clearance pathways for oxidatively modified proteins may be induced and serve in the immediate cellular response to preserve the epithelial layer. To test this, airway epithelial cells were obtained from individuals under ambient oxygen conditions and after breathing 100% oxygen for 12 h. Gene expression profiling identified induction of genes in the chaperone and proteasome-ubiquitin-conjugation pathways that together comprise an integrated cellular response to manage and degrade damaged proteins. Analyses also revealed gene expression changes associated with oxidoreductase function, cell cycle regulation, and ATP synthesis. Increased HSP70, protein ubiquitination, and intracellular ATP were validated in cells exposed to hyperoxia in vitro. Inhibition of proteasomal degradation revealed the importance of accelerated protein catabolism for energy production of cells exposed to hyperoxia. Thus, the human airway early response to hyperoxia relies predominantly upon induction of cytoprotective chaperones and the ubiquitin-proteasome–dependent protein degradation system to maintain airway homeostatic integrity.
doi:10.1165/rcmb.2005-0251OC
PMCID: PMC2643263  PMID: 16690988
airways; gene expression; hyperoxia; proteasome; ubiquitin
11.  Correlation of Systemic Superoxide Dismutase Deficiency to Airflow Obstruction in Asthma 
Rationale: Increased oxidative stress and decreased superoxide dismutase (SOD) activity in the asthmatic airway are correlated to airflow limitation and hyperreactivity. We hypothesized that asthmatic individuals with higher levels of oxidative stress may have greater loss of SOD activity, which would be reflected systemically in loss of circulating SOD activity and clinically by development of severe asthma and/or worsening airflow limitation. Methods: To investigate this, serum SOD activity and proteins, the glutathione peroxidase/glutathione antioxidant system, and oxidatively modified amino acids were measured in subjects with asthma and healthy control subjects. Results: SOD activity, but not Mn-SOD or Cu,Zn-SOD protein, was lower in asthmatic serum as compared with control, and activity loss was significantly related to airflow limitation. Further, serum SOD activity demonstrated an inverse correlation with circulating levels of 3-bromotyrosine, a posttranslational modification of proteins produced by the eosinophil peroxidase system of eosinophils. Exposure of purified Cu,Zn-SOD to physiologically relevant levels of eosinophil peroxidase-generated reactive brominating species, reactive nitrogen species, or tyrosyl radicals in vitro confirmed that eosinophil-derived oxidative pathways promote enzyme inactivation. Conclusion: These findings are consistent with greater oxidant stress in asthma leading to greater inactivation of SOD, which likely amplifies inflammation and progressive airflow obstruction.
doi:10.1164/rccm.200502-180OC
PMCID: PMC2718470  PMID: 15883124
asthma; superoxide dismutase; glutathione; pulmonary functions; peroxidase
12.  Detection of Lung Cancer by Sensor Array Analyses of Exhaled Breath 
Rationale: Electronic noses are successfully used in commercial applications, including detection and analysis of volatile organic compounds in the food industry. Objectives: We hypothesized that the electronic nose could identify and discriminate between lung diseases, especially bronchogenic carcinoma. Methods: In a discovery and training phase, exhaled breath of 14 individuals with bronchogenic carcinoma and 45 healthy control subjects or control subjects without cancer was analyzed. Principal components and canonic discriminant analysis of the sensor data was used to determine whether exhaled gases could discriminate between cancer and noncancer. Discrimination between classes was performed using Mahalanobis distance. Support vector machine analysis was used to create and apply a cancer prediction model prospectively in a separate group of 76 individuals, 14 with and 62 without cancer. Main Results: Principal components and canonic discriminant analysis demonstrated discrimination between samples from patients with lung cancer and those from other groups. In the validation study, the electronic nose had 71.4% sensitivity and 91.9% specificity for detecting lung cancer; positive and negative predictive values were 66.6 and 93.4%, respectively. In this population with a lung cancer prevalence of 18%, positive and negative predictive values were 66.6 and 94.5%, respectively. Conclusion: The exhaled breath of patients with lung cancer has distinct characteristics that can be identified with an electronic nose. The results provide feasibility to the concept of using the electronic nose for managing and detecting lung cancer.
doi:10.1164/rccm.200409-1184OC
PMCID: PMC2718462  PMID: 15750044
breath tests; bronchogenic cancer; electronic nose; volatile organic compounds
13.  Asthma Is More Severe in Older Adults 
PLoS ONE  2015;10(7):e0133490.
Background
Severe asthma occurs more often in older adult patients. We hypothesized that the greater risk for severe asthma in older individuals is due to aging, and is independent of asthma duration.
Methods
This is a cross-sectional study of prospectively collected data from adult participants (N=1130; 454 with severe asthma) enrolled from 2002 – 2011 in the Severe Asthma Research Program.
Results
The association between age and the probability of severe asthma, which was performed by applying a Locally Weighted Scatterplot Smoother, revealed an inflection point at age 45 for risk of severe asthma. The probability of severe asthma increased with each year of life until 45 years and thereafter increased at a much slower rate. Asthma duration also increased the probability of severe asthma but had less effect than aging. After adjustment for most comorbidities of aging and for asthma duration using logistic regression, asthmatics older than 45 maintained the greater probability of severe asthma [OR: 2.73 (95 CI: 1.96; 3.81)]. After 45, the age-related risk of severe asthma continued to increase in men, but not in women.
Conclusions
Overall, the impact of age and asthma duration on risk for asthma severity in men and women is greatest over times of 18-45 years of age; age has a greater effect than asthma duration on risk of severe asthma.
doi:10.1371/journal.pone.0133490
PMCID: PMC4511639  PMID: 26200463
14.  Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis 
PLoS ONE  2015;10(7):e0132007.
Asthma, a chronic inflammatory airway disease, is typified by high levels of TH2-cytokines and excessive generation of reactive nitrogen and oxygen species, which contribute to bronchial epithelial injury and airway remodeling. While immune function plays a major role in the pathogenesis of the disease, accumulating evidence suggests that altered cellular metabolism is a key determinant in the predisposition and disease progression of asthma. Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic. However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients. Platelets are easily accessible blood cells that are known to propagate airway inflammation in asthma. Here we perform a bioenergetic screen of platelets from asthmatic and healthy individuals and demonstrate that asthmatic platelets show a decreased reliance on glycolytic processes and have increased tricarboxylic acid cycle activity. These data demonstrate a systemic alteration in asthma and are consistent with prior reports suggesting that oxidative phosphorylation is more efficient asthmatic individuals. The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients. Further, these data suggest that platelets are potentially a good model for the monitoring of bioenergetic changes in asthma.
doi:10.1371/journal.pone.0132007
PMCID: PMC4492492  PMID: 26147848
15.  Impaired Global Right Ventricular Longitudinal Strain Predicts Long-Term Adverse Outcomes in Patients with Pulmonary Arterial Hypertension 
Background
New 2-dimensional strain echocardiography enables quantification of right ventricular (RV) mechanics by assessing global longitudinal strain of RV (GLSRV) in patients with pulmonary arterial hypertension (PAH). However, the prognostic significance of impaired GLSRV is unclear in these patients.
Methods
Comprehensive echocardiography was performed in 51 consecutive PAH patients without atrial fibrillation (40 females, 48 ± 14 years old) with long-term follow-up. GLSRV was measured with off-line with velocity vector imaging (VVI, Siemens Medical System, Mountain View, CA, USA).
Results
GLSRV showed significant correlation with RV fractional area change (r = -0.606, p < 0.001), tricuspid annular plane systolic excursion (r = -0.579, p < 0.001), and RV Tei index (r = 0.590, p < 0.001). It showed significant correlations with pulmonary vascular resistance (r = 0.469, p = 0.001) and B-natriuretic peptide concentration (r = 0.351, p = 0.012). During a clinical followup time (45 ± 15 months), 20 patients experienced one or more adverse events (12 death, 2 lung transplantation, and 15 heart failure hospitalization). After multivariate analysis, age [hazard ratio (HR) = 2.343, p = 0.040] and GLSRV (HR = 2.122, p = 0.040) were associated with adverse clinical events. Age (HR = 3.200, p = 0.016) and GLSRV (HR = 2.090, p = 0.042) were also significant predictors of death. Impaired GLSRV (≥ -15.5%) was associated with lower event-free survival (HR = 4.906, p = 0.001) and increased mortality (HR = 8.842, p = 0.005).
Conclusion
GLSRV by VVI showed significant correlations with conventional echocardiographic parameters indicating RV systolic function. Lower GLSRV (≥ -15.5%) was significantly associated with presence of adverse clinical events and deaths in PAH patients.
doi:10.4250/jcu.2015.23.2.91
PMCID: PMC4486184  PMID: 26140151
Pulmonary arterial hypertension; Right ventricle; Strain echocardiography
18.  Effect of RareGenetic Variants in the β2 Adrenergic Receptor Geneon the Risk for Exacerbations and Symptom Control During Long-Acting Beta Agonist Treatment in a Multi-Ethnic Asthma Population 
The Lancet. Respiratory medicine  2014;2(3):204-213.
Background
Severe adverse life-threatening events associated with long-acting beta agonists (LABA) use have caused the FDA to review LABA safety which has resulted in a boxed warning and a mandatory LABA safety study in 46,800 asthmatics. Identification of an at-risk, susceptible subpopulation using predictive biomarkers is critical in understanding LABA safety. The β2-adrenergic receptor gene (ADRB2) contains a common, nonsynonymous single nucleotide polymorphism, Gly16Arg, that is unlikely to account for rare, life-threatening events. We hypothesize that rare ADRB2 variants with strong effects modulate therapeutic responses to long-acting beta agonist (LABA) therapy and contribute to rare, severe adverse events.
Methods
ADRB2 was sequenced in 197 African Americans, 191 non-Hispanic Whites, and 73 Puerto Ricans. Sequencing identified six rare variants which were genotyped in 1,165 asthmatics (total=1,626). The primary hypothesis was that severe asthma exacerbations requiring hospitalization were associated with rare ADRB2 variants. Replication was performed in 659 non-Hispanic White asthma subjects.
Findings
Asthmatics receiving LABA with a rare variant had increased asthma-related hospitalizations (meta-analysis for all ethnic groups: p=2·83 × 10−4), specifically LABA-treated non-Hispanic Whites with the rare Ile164 allele (only rare variant in Whites, OR4·48, 95% CI 1·40–14·0, p=0·01) and African Americans with a 25 base-pair promoter polynucleotide insertion (OR 13·43, 95% CI 2·02–265·4, p=0·006). The subset of non-Hispanic Whites and African Americans receiving LABAs with these rare variants had increased exacerbations requiring urgent outpatient healthcare visits (non-Hispanic Whites with or without the rare Ile164 allele: 2·6 visits versus 1·1 visits, p=8·4 × 10−7 and African Americans with or without the rare insertion: 3·7 visits versus 2·4 visits, 0·01), and more frequently were treated with chronic systemic corticosteroids (OR4·2, 95% CI1·4–14, p=0·01 and OR12·83, 95% CI 1·96–251·9, 0·006). Non-Hispanic Whites from the primary and replication cohorts with the rare Ile164 allele were more than twice as likely to experience uncontrolled, persistent symptoms during LABA treatment (p=0·008–0·04).
Interpretation
Rare ADRB2 variants are associated with adverse events during LABA therapy and should be evaluated in large clinical trials including the current FDA-mandated LABA safety study.
doi:10.1016/S2213-2600(13)70289-3
PMCID: PMC4053167  PMID: 24621682
19.  Arginine metabolic endotypes in pulmonary arterial hypertension 
Pulmonary Circulation  2015;5(1):124-134.
Decreased synthesis of nitric oxide (NO) by NO synthases (NOS) is believed to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Multiple factors may contribute to decreased NO bioavailability, including increased activity of arginase, the enzyme that converts arginine to ornithine and urea, which may compete with NOS for arginine; inadequate de novo arginine production from citrulline; and increased concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. We hypothesized that PAH patients with the lowest arginine availability secondary to increased arginase activity and/or inadequate de novo arginine synthesis might have a slower rate of NO synthesis and greater pulmonary vascular resistance. Nine patients with group 1 PAH and 10 healthy controls were given primed, constant intravenous infusions of 15N2-arginine, 13C,2H4-citrulline, 15N2-ornithine, and 13C-urea in the postabsorptive state. The results showed that, compared with healthy controls, PAH patients had a tendency toward increased arginine clearance and ornithine flux but no difference in arginine and citrulline flux, de novo arginine synthesis, or NO synthesis. Arginine-to-ADMA ratio was increased in PAH patients. Two endotypes of patients with low and high arginase activity were identified; compared with the low-arginase group, the patients with high arginase had increased arginine flux, slower NO synthesis, and lower plasma concentrations of ADMA. These results demonstrate that increased breakdown of arginine by arginase occurs in PAH and affects NO synthesis. Furthermore, there is no compensatory increase in de novo arginine synthesis to overcome this increased utilization of arginine by arginase.
doi:10.1086/679720
PMCID: PMC4405713  PMID: 25992277
nitric oxide; arginase; asymmetric dimethylarginine; ornithine
20.  An Official American Thoracic Society Statement: Pulmonary Hypertension Phenotypes 
Background: Current classification of pulmonary hypertension (PH) is based on a relatively simple combination of patient characteristics and hemodynamics. This limits customization of treatment, and lacks the clarity of a more granular identification based on individual patient phenotypes. Rapid advances in mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define PH phenotypes on the basis of biomarkers, advanced imaging, and pathobiology. This document organizes our current understanding of PH phenotypes and identifies gaps in our knowledge.
Methods: A multidisciplinary committee with expertise in clinical care (pulmonary, cardiology, pediatrics, and pathology), clinical research, and/or basic science in the areas of PH identified important questions and reviewed and synthesized the literature.
Results: This document describes selected PH phenotypes and serves as an initial platform to define additional relevant phenotypes as new knowledge is generated. The biggest gaps in our knowledge stem from the fact that our present understanding of PH phenotypes has not come from any particularly organized effort to identify such phenotypes, but rather from reinterpreting studies and reports that were designed and performed for other purposes.
Conclusions: Accurate phenotyping of PH can be used in research studies to increase the homogeneity of study cohorts. Once the ability of the phenotypes to predict outcomes has been validated, phenotyping may also be useful for determining prognosis and guiding treatment. This important next step in PH patient care can optimally be addressed through a consortium of study sites with well-defined goals, tasks, and structure. Planning and support for this could include the National Institutes of Health and the U.S. Food and Drug Administration, with industry and foundation partnerships.
doi:10.1164/rccm.201311-1954ST
PMCID: PMC4291177  PMID: 24484330
biomarkers; consortium; metabolism; pathobiology; pulmonary circulation
21.  Relevant Issues in the Pathology and Pathobiology of Pulmonary Hypertension 
Knowledge of the pathobiology of pulmonary hypertension continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary arteries and veins in the different forms of this syndrome. Although pulmonary hypertension primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in pulmonary hypertension is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that while vasospasm plays a role, pulmonary hypertension is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor (BMPR)2 or activin-like kinase (Alk)-1 or epigenetically-inherited (as a result of epigenetic silencing of genes such as superoxide dismutase 2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild pulmonary hypertension in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of role of pulmonary inflammation in the initiation and promotion of pulmonary hypertension has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of pulmonary hypertension, including a role for bone marrow and circulating progenitor cells and microRNAs. Continued interest in the interface of the genetic basis of pulmonary hypertension and cellular and molecular pathogenetic links should expand further our understanding of the disease.
doi:10.1016/j.jacc.2013.10.025
PMCID: PMC3970402  PMID: 24355640
inflammation; metabolism; pulmonary arteries; pulmonary veins
22.  Bronchial Thermoplasty – Long Term Safety and Effectiveness in Severe Persistent Asthma 
Background
Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma.
Objective
To assess effectiveness and safety of BT in asthma patients 5 years post therapy.
Methods
BT-treated subjects from the Asthma Intervention Research 2 (AIR2) Trial (ClinicalTrials.gov NCT01350414) were evaluated annually for 5 years to assess long-term safety of BT and durability of treatment effect. Outcomes assessed post-BT included severe exacerbations, adverse events, healthcare utilization, spirometry data, and high resolution computed tomography (HRCT) scans.
Results
162/190 BT-treated subjects (85.3%) from the AIR2 Trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and Emergency Room visits, and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months prior to BT treatment (average 5 year reduction in proportions: 44% for exacerbations and 78% for ER visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in Years 2 through 5 as compared to the first year after BT. Pre-BD FEV1 values remained stable between years 1 and 5 after BT, despite a 17% reduction in average daily inhaled corticosteroid dose. HRCT scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT.
Conclusions
These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ER visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking ICS (inhaled corticosteroids) and LABA (long-acting-β2-agonists).
doi:10.1016/j.jaci.2013.08.009
PMCID: PMC4114404  PMID: 23998657
Bronchial thermoplasty; asthma; Bronchoscopic procedure; Alair System; asthma exacerbation
24.  Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients 
Background
Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
Objective
We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.
Methods
Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses.
Results
Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV1 (P < 10−4) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10−11). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10−7) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. TH2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function.
Conclusion
Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. TH1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.
doi:10.1016/j.jaci.2013.01.051
PMCID: PMC3746327  PMID: 23541324
Lung function; FEV1; asthma; TH1; IL12A; IL12RB1; STAT4; IRF2
25.  Coenzyme Q supplementation in pulmonary arterial hypertension 
Redox Biology  2014;2:884-891.
Mitochondrial dysfunction is a fundamental abnormality in the vascular endothelium and smooth muscle of patients with pulmonary arterial hypertension (PAH). Because coenzyme Q (CoQ) is essential for mitochondrial function and efficient oxygen utilization as the electron carrier in the inner mitochondrial membrane, we hypothesized that CoQ would improve mitochondrial function and benefit PAH patients. To test this, oxidized and reduced levels of CoQ, cardiac function by echocardiogram, mitochondrial functions of heme synthesis and cellular metabolism were evaluated in PAH patients (N=8) in comparison to healthy controls (N=7), at baseline and after 12 weeks oral CoQ supplementation. CoQ levels were similar among PAH and control individuals, and increased in all subjects with CoQ supplementation. PAH patients had higher CoQ levels than controls with supplementation, and a tendency to a higher reduced-to-oxidized CoQ ratio. Cardiac parameters improved with CoQ supplementation, although 6-minute walk distances and BNP levels did not significantly change. Consistent with improved mitochondrial synthetic function, hemoglobin increased and red cell distribution width (RDW) decreased in PAH patients with CoQ, while hemoglobin declined slightly and RDW did not change in healthy controls. In contrast, metabolic and redox parameters, including lactate, pyruvate and reduced or oxidized gluthathione, did not change in PAH patients with CoQ. In summary, CoQ improved hemoglobin and red cell maturation in PAH, but longer studies and/or higher doses with a randomized placebo-controlled controlled design are necessary to evaluate the clinical benefit of this simple nutritional supplement.
Graphical abstract
Highlights
•Pulmonary arterial hypertension (PAH) is characterized by mitochondrial dysfunction.•Co-enzymeQ (CoQ) is important for mitochondria function.•CoQ supplementation improved heart function and red cell production in PAH.•The findings support the concept of mitochondrial-targeted therapies for PAH.
doi:10.1016/j.redox.2014.06.010
PMCID: PMC4143816  PMID: 25180165
Pulmonary hypertension; Mitochondria; Coenzyme Q; Hemoglobin; Heart failure; Metabolism

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