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1.  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.
PMCID: PMC4291177  PMID: 24484330
biomarkers; consortium; metabolism; pathobiology; pulmonary circulation
2.  Causes and Circumstances of Death in Pulmonary Arterial Hypertension 
Rationale: The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH).
Objectives: We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH.
Methods: All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included.
Measurements and Main Results: PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives.
Conclusions: Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.
PMCID: PMC3778730  PMID: 23600433
pulmonary hypertension; outcome assessment; cause of death
3.  Severe Asthma 
The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure–function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.
PMCID: PMC3297096  PMID: 22095547
asthma; remodeling; inflammation; bronchoscopy; imaging
4.  Plasma Levels of High-Density Lipoprotein Cholesterol and Outcomes in Pulmonary Arterial Hypertension 
Rationale: High-density lipoprotein cholesterol (HDL-C) promotes healthy vascular function, and it is decreased in insulin resistance. Insulin resistance predisposes to pulmonary vascular disease.
Objectives: We hypothesized that HDL-C is associated with clinical outcomes in pulmonary arterial hypertension (PAH).
Methods: Plasma HDL-C concentrations were measured in 69 patients with PAH (age, 46.7 ± 12.9 yr; female, 90%) and 229 control subjects (age, 57 ± 13 yr; female, 48%). Clinical outcomes of interest included hospitalization for PAH, lung transplantation, and all-cause mortality. Survival and time to clinical worsening curves were derived by the Kaplan-Meier method. Cox regression modeling of outcome versus HDL-C with individual covariate adjustments was performed.
Measurement and Main Results: HDL-C was low in subjects with PAH compared with control subjects (median, interquartile range: PAH: 36, 29–40 mg/dl; control subjects: 49, 40–60 mg/dl; P < 0.001). An HDL-C level of 35 mg/dl discriminated survivors from nonsurvivors, with a sensitivity of 100% and specificity of 60%. After a median follow-up of 592 days, high HDL-C was associated with decreased mortality (hazard ratio for every 5-mg/dl increase in HDL-C, 0.643; 95% confidence interval, 0.504–0.822; P = 0.001) and less clinical worsening (hazard ratio for every 5-mg/dl increase in HDL-C, 0.798; 95% confidence interval, 0.663–0.960; P = 0.02). HDL-C remained a significant predictor of survival after adjusting for cardiovascular risk factors, C-reactive protein, indices of insulin resistance, and severity of PAH (all P < 0.05).
Conclusions: Low plasma HDL-C is associated with higher mortality and clinical worsening in PAH. This association does not appear to be explained by underlying cardiovascular risk factors, insulin resistance, or the severity of PAH.
PMCID: PMC2937236  PMID: 20448092
hypertension; pulmonary; cholesterol; high-density lipoprotein; mortality
5.  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.
PMCID: PMC2874447  PMID: 20133930
nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath
6.  Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program 
Rationale: The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma.
Objectives: To identify novel asthma phenotypes using an unsupervised hierarchical cluster analysis.
Methods: Reduction of the initial 628 variables to 34 core variables was achieved by elimination of redundant data and transformation of categorical variables into ranked ordinal composite variables. Cluster analysis was performed on 726 subjects.
Measurements and Main Results: Five groups were identified. Subjects in Cluster 1 (n = 110) have early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 (n = 321) consists of subjects with early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization. Cluster 3 (n = 59) is a unique group of mostly older obese women with late-onset nonatopic asthma, moderate reductions in FEV1, and frequent oral corticosteroid use to manage exacerbations. Subjects in Clusters 4 (n = 120) and 5 (n = 116) have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids.
Conclusions: Five distinct clinical phenotypes of asthma have been identified using unsupervised hierarchical cluster analysis. All clusters contain subjects who meet the American Thoracic Society definition of severe asthma, which supports clinical heterogeneity in asthma and the need for new approaches for the classification of disease severity in asthma.
PMCID: PMC2822971  PMID: 19892860
asthma phenotype; definition; cluster analysis; severe asthma
7.  Effects of the Menstrual Cycle on Lung Function Variables in Women with Asthma 
Rationale: Angiogenesis is a defining pathologic feature of airway remodeling and contributes to asthma severity. Women experience changes in asthma control over the menstrual cycle, a time when vessels routinely form and regress under the control of angiogenic factors. One vital function modulated over the menstrual cycle in healthy women is gas transfer, and this has been related to angiogenesis and cyclic expansion of the pulmonary vascular bed.
Objectives: We hypothesized that changes in gas transfer and the pulmonary vascular bed occur in women with asthma over the menstrual cycle and are associated with worsening airflow obstruction.
Methods: Twenty-three women, 13 with asthma and 10 healthy control subjects, were evaluated over the menstrual cycle with weekly measures of spirometry, gas transfer, nitric oxide, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors.
Measurements and Main Results: Airflow and lung diffusing capacity varied over the menstrual cycle with peak levels during menses that subsequently declined to nadir in early luteal phase. In contrast to healthy women, changes in lung diffusing capacity (DlCO) were associated with changes in membrane diffusing capacity and DlCO was not related to proangiogenic factors. DlCO did not differ between the two groups, although methemoglobin and carboxyhemoglobin were higher in women with asthma than in healthy women.
Conclusions: Women with asthma experience cyclic changes in airflow as well as gas transfer and membrane diffusing capacity supportive of a hormonal effect on lung function.
PMCID: PMC2731807  PMID: 19520904
gas transfer; angiogenesis; asthma; menstrual cycle; proangiogenic progenitor cell
8.  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.
PMCID: PMC2556449  PMID: 18635886
asthma; arginine; arginase; nitric oxide; methylarginine
9.  Abnormalities in Nitric Oxide and Its Derivatives in Lung Cancer 
Rationale: A cellular prooxidant state promotes cells to neoplastic growth, in part because of modification of proteins and their functions. Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer. Objective: To determine the alteration in these NO derivatives and the role they may play in contributing to lung carcinogenesis. Methods: We analyzed levels of NO, nitrite (NO2−), nitrate (NO3−), and the location of the protein nitration and identified the proteins that are modified. Measurements and Main Results: Although exhaled NO and NO2− were increased, endothelial NO synthase or inducible NO synthase expression was similar in the tumor and tumor-free regions. However, immunohistochemistry showed that nitrotyrosine was increased in the tumor relative to non–tumor-bearing sections. We used proteomics to identify the modified proteins (two-dimensional polyacrylamide gel electrophoresis; mass spectrometry). Both the degree of nitration and the protein nitration profile were altered. We identified more than 25 nitrated proteins, including metabolic enzymes, structural proteins, and proteins involved in prevention of oxidative damage. Alterations of the biology of NO metabolites and nitration of proteins may contribute to the mutagenic processes and promote carcinogenesis. Conclusions: This study provides evidence in favor of a role for reactive nitrogen and oxygen species in lung cancer.
PMCID: PMC2718532  PMID: 15947282
lung cancer; nitric oxide; nitrotyrosine; protein nitration; proteomics
10.  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.
PMCID: PMC2718470  PMID: 15883124
asthma; superoxide dismutase; glutathione; pulmonary functions; peroxidase
11.  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.
PMCID: PMC2718462  PMID: 15750044
breath tests; bronchogenic cancer; electronic nose; volatile organic compounds

Results 1-11 (11)