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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.
doi:10.1164/rccm.201311-1954ST
PMCID: PMC4291177  PMID: 24484330
biomarkers; consortium; metabolism; pathobiology; pulmonary circulation
2.  Strategic Plan for Lung Vascular Research 
The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype–phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes.
doi:10.1164/rccm.201006-0869WS
PMCID: PMC3029941  PMID: 20833821
right ventricle; pulmonary hypertension; metabolism; genomics; phenotyping
3.  Hemodynamic Predictors of Survival in Scleroderma-related Pulmonary Arterial Hypertension 
Rationale: Pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc) has a poorer prognosis compared with other forms of PAH for reasons that remain unexplained.
Objectives: To identify risk factors of mortality in a well-characterized cohort of patients with PAH related to systemic sclerosis (SSc-PAH).
Methods: Seventy-six consecutive patients with SSc (64 women and 12 men; mean age 61 ± 11 yr) were diagnosed with PAH by heart catheterization in a single center, starting in January 2000, and followed over time. Kaplan-Meier estimates were calculated and mortality risk factors were analyzed.
Measurements and Main Results: Forty (53%) patients were in World Health Organization functional class III or IV. Mean pulmonary artery pressure was 41 ± 11 mm Hg, pulmonary vascular resistance (PVR) was 8.6 ± 5.6 Wood units, and cardiac index was 2.4 ± 0.7 L/min/m2. Median follow-up time was 36 months, with 42 deaths observed. Survival estimates were 85%, 72%, 67%, 50%, and 36% at 1, 2, 3, 4, and 5 years, respectively. Multivariate analysis identified PVR (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03–1.18; P < 0.01), stroke volume index (HR, 0.94; 95% CI, 0.89–0.99; P = 0.02), and pulmonary arterial capacitance (HR, 0.43; 95% CI, 0.20–0.91; P = 0.03) as strong predictors of survival. An estimated glomerular filtration rate less than 60 ml/min/1.73 m2 portended a threefold risk of mortality.
Conclusions: Our results suggest that specific components of right ventricular dysfunction and renal impairment contribute to increased mortality in SSc-PAH. Understanding the mechanisms of right ventricular dysfunction in response to increased afterload should lead to improved targeted therapy in these patients.
doi:10.1164/rccm.200912-1820OC
PMCID: PMC2913238  PMID: 20339143
4.  Systemic Sclerosis-associated Pulmonary Arterial Hypertension 
Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases, including systemic sclerosis (SSc), where it has a dramatic impact on the clinical course and overall survival and is the single most common cause of death in patients afflicted with this syndrome. Although remarkable advances have been achieved in elucidating the pathogenesis of PAH over the past 2 decades, leading to the development of disease-targeted therapies for the idiopathic form of this condition (IPAH), the response to therapy is suboptimal in SSc-related PAH (SSc-PAH), and survival remains very poor. Factors accounting for striking clinical and prognostic differences between these two syndromes are unclear but may include a more pronounced autoimmune, cellular, and inflammatory response, and a higher prevalence of comorbidities in SSc-PAH, including cardiac and pulmonary venous and parenchymal involvement. Furthermore, currently available markers of disease severity and clinical tools to assess response to therapy, which may be reliable in IPAH, are either limited or lacking in SSc-PAH. Thus, a more focused approach, including a better understanding of the pathogenesis and genetic factors underlying the development of SSc-PAH, a search for more specific and reliable tools to adequately assess functional impairment and monitor therapy, as well as the design of novel targeted therapies, are all urgently required to alter the dismal course of this syndrome.
doi:10.1164/rccm.200909-1331PP
PMCID: PMC2894407  PMID: 20194816
scleroderma; pulmonary hypertension; prognostic factors
5.  The Triterpenoid CDDO-Imidazolide Confers Potent Protection against Hyperoxic Acute Lung Injury in Mice 
Rationale: Oxygen supplementation (e.g., hyperoxia) is used to support critically ill patients with noninfectious and infectious acute lung injury (ALI); however, hyperoxia exposure can potentially further contribute to and/or perpetuate preexisting ALI. Thus, developing novel therapeutic agents to minimize the side effects of hyperoxia is essential to improve the health of patients with severe ALI and respiratory dysfunction. We have previously shown that mice with a genetic disruption of the Nrf2 transcription factor, which squelches cellular stress by up-regulating the induction of several antioxidant enzymes and proteins, have greater susceptibility to hyperoxic lung injury. Moreover, we have recently demonstrated that Nrf2-deficiency impairs the resolution of lung injury and inflammation after nonlethal hyperoxia exposure.
Objectives: To test the hypothesis that amplification of endogenous Nrf2 activity would prevent or dampen ALI induced by hyperoxia.
Methods: Here, we tested our hypothesis using a synthetic triterpenoid compound CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole) in Nrf2-sufficient and Nrf2-deficient mice subjected to hyperoxia-induced ALI.
Measurements and Main Results: We demonstrate that oral administration of CDDO-Im at a dose of 30 μmol/kg body weight during the hyperoxic exposure is sufficient to markedly attenuate hyperoxia-induced ALI in Nrf2-sufficient but not Nrf2-deficient mice. This protection by the CDDO-Im against hyperoxic insult was accompanied by increased levels of Nrf2-regulated cytoprotective gene expression and reduced levels of DNA damage in the lung.
Conclusions: These results suggest that up-regulation of Nrf2 signaling by CDDO-Im or its analogs may provide a novel therapeutic strategy to minimize the adverse effects of hyperoxia.
doi:10.1164/rccm.200905-0670OC
PMCID: PMC2773914  PMID: 19679692
Nrf2; Keap1; antioxidants; stress response
6.  Accuracy of Doppler Echocardiography in the Hemodynamic Assessment of Pulmonary Hypertension 
Rationale: Transthoracic Doppler echocardiography is recommended for screening for the presence of pulmonary hypertension (PH). However, some recent studies have suggested that Doppler echocardiographic pulmonary artery pressure estimates may frequently be inaccurate.
Objectives: Evaluate the accuracy of Doppler echocardiography for estimating pulmonary artery pressure and cardiac output.
Methods: We conducted a prospective study on patients with various forms of PH who underwent comprehensive Doppler echocardiography within 1 hour of a clinically indicated right-heart catheterization to compare noninvasive hemodynamic estimates with invasively measured values.
Measurements and Main Results: A total of 65 patients completed the study protocol. Using Bland-Altman analytic methods, the bias for the echocardiographic estimates of the pulmonary artery systolic pressure was −0.6 mm Hg with 95% limits of agreement ranging from +38.8 to −40.0 mm Hg. Doppler echocardiography was inaccurate (defined as being greater than ±10 mm Hg of the invasive measurement) in 48% of cases. Overestimation and underestimation of pulmonary artery systolic pressure by Doppler echocardiography occurred with a similar frequency (16 vs. 15 instances, respectively). The magnitude of pressure underestimation was greater than overestimation (−30 ± 16 vs. +19 ± 11 mm Hg; P = 0.03); underestimates by Doppler also led more often to misclassification of the severity of the PH. For cardiac output measurement, the bias was −0.1 L/min with 95% limits of agreement ranging from +2.2 to −2.4 L/min.
Conclusions: Doppler echocardiography may frequently be inaccurate in estimating pulmonary artery pressure and cardiac output in patients being evaluated for PH.
doi:10.1164/rccm.200811-1691OC
PMCID: PMC2720125  PMID: 19164700
echocardiography; pulmonary hypertension; pulmonary systolic pressure; cardiac output; accuracy
7.  Hyponatremia Predicts Right Heart Failure and Poor Survival in Pulmonary Arterial Hypertension 
Rationale: Hyponatremia is associated with decompensated heart failure and poor prognosis in patients with left ventricular systolic dysfunction.
Objectives: We sought to determine if hyponatremia is associated with right heart failure and worse prognosis in patients with pulmonary arterial hypertension (PAH).
Methods: We prospectively followed 40 patients with PAH and examined the relationship between serum sodium and right heart function as well as survival.
Measurements and Main Results: Subjects with hyponatremia (Na ⩽ 136 mEq/L) were more symptomatic (11/13 World Health Organization [WHO] class III/IV vs. 12/27 WHO class III/IV; P = 0.02), had more peripheral edema (69 vs. 26%; P = 0.009), and had higher hospitalization rates (85 vs. 41%; P = 0.009) than normonatremic subjects. Hyponatremic subjects had higher right atrial pressure (14 ± 6 vs. 9 ± 3 mm Hg; P < 0.001), lower stroke volume index (21 ± 7 vs. 32 ± 10 ml/m2; P < 0.01), larger right ventricular:left ventricular area ratio (1.8 ± 0.4 vs. 1.3 ± 0.4; P < 0.001), and lower tricuspid annular plane systolic excursion (1.4 ± 0.3 vs. 2.0 ± 0.6 cm; P = 0.001), despite similar mean pulmonary artery pressure (49 ± 10 vs. 47 ± 12 mm Hg; P = 0.60). The 1- and 2-year survival estimates were 93% (95% confidence interval [CI], 73–98%) and 85% (95% CI, 65–94%), and 38% (95% CI, 14–63%) and 15% (95% CI, 2–39%) for normonatremic and hyponatremic subjects, respectively (log-rank χ2 = 25.19, P < 0.001). The unadjusted risk of death (hazard ratio) in hyponatremic compared with normonatremic subjects was 10.16 (95% CI, 3.42–30.10, P < 0.001). Hyponatremia predicted outcome after adjusting for WHO class, diuretic use, as well as right atrial pressure and cardiac index.
Conclusions: Hyponatremia is strongly associated with right heart failure and poor survival in PAH.
doi:10.1164/rccm.200712-1876OC
PMCID: PMC2427057  PMID: 18356560
hyponatremia; pulmonary heart disease; pulmonary hypertension; heart failure
8.  Genetic and Pharmacologic Evidence Links Oxidative Stress to Ventilator-induced Lung Injury in Mice 
Rationale: Mechanical ventilation (MV) is an indispensable therapy for critically ill patients with acute lung injury and the adult respiratory distress syndrome. However, the mechanisms by which conventional MV induces lung injury remain unclear.
Objectives: We hypothesized that disruption of the gene encoding Nrf2, a transcription factor that regulates the induction of several antioxidant enzymes, enhances susceptibility to ventilator-induced lung injury (VILI) and that antioxidant supplementation attenuates this effect.
Methods: To test our hypothesis and to examine the relevance of oxidative stress in VILI, we assessed lung injury and inflammatory responses in Nrf2-deficient (Nrf2−/−) mice and wild-type (Nrf2+/+) mice after an acute (2-h) injurious model of MV with or without administration of antioxidant.
Measurements and Main Results: Nrf2−/− mice displayed greater levels of lung alveolar and vascular permeability and inflammatory responses to MV as compared with Nrf2+/+ mice. Nrf2 deficiency enhances the levels of several proinflammatory cytokines implicated in the pathogenesis of VILI. We found diminished levels of critical antioxidant enzymes and redox imbalance by MV in the lungs of Nrf2−/− mice; however, antioxidant supplementation to Nrf2−/− mice remarkably attenuated VILI. When subjected to a clinically relevant prolong period of MV, Nrf2−/− mice displayed greater levels of VILI than Nrf2+/+ mice. Expression profiling revealed lack of induction of several VILI genes, stress response and solute carrier proteins, and phosphatases in Nrf2−/− mice.
Conclusions: Our data demonstrate for the first time a critical role for Nrf2 in VILI, which confers protection against cellular responses induced by MV by modulating oxidative stress.
doi:10.1164/rccm.200701-060OC
PMCID: PMC2176106  PMID: 17901416
acute lung injury; antioxidant enzymes; mechanical ventilation; Nrf2; inflammation
9.  Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury 
Rationale: Inducible nitric oxide synthase (iNOS) has been implicated in the development of acute lung injury. Recent studies indicate a role for mechanical stress in iNOS and endothelial NOS (eNOS) regulation. Objectives: This study investigated changes in lung NOS expression and activity in a mouse model of ventilator-induced lung injury. Methods: C57BL/6J (wild-type [WT]) and iNOS-deficient (iNOS−/−) mice received spontaneous ventilation (control) or mechanical ventilation (MV; VT of 7 and 20 ml/kg) for 2 hours, after which NOS gene expression and activity were determined and pulmonary capillary leakage assessed by the Evans blue albumin assay. Results: iNOS mRNA and protein expression was absent in iNOS−/− mice, minimal in WT control mice, but significantly upregulated in response to 2 hours of MV. In contrast, eNOS protein was decreased in WT mice, and nonsignificantly increased in iNOS−/− mice, as compared with control animals. iNOS and eNOS activities followed similar patterns in WT and iNOS−/− mice. MV caused acute lung injury as suggested by cell infiltration and nitrotyrosine accumulation in the lung, and a significant increase in bronchoalveolar lavage cell count in WT mice, findings that were reduced in iNOS−/− mice. Finally, Evans blue albumin accumulation in lungs of WT mice was significant (50 vs. 15% increase in iNOS−/− mice compared with control animals) in response to MV and was prevented by treatment of the animals with the iNOS inhibitor aminoguanidine. Conclusion: Taken together, our results indicate that iNOS gene expression and activity are significantly upregulated and contribute to lung edema in ventilator-induced lung injury.
doi:10.1164/rccm.200411-1547OC
PMCID: PMC2718528  PMID: 15937288
inducible nitric oxide synthase; lung permeability; mechanical ventilation

Results 1-9 (9)