An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease.

BACKGROUND: In adults with sickle cell disease (SCD), an increased tricuspid regurgitant velocity (TRV) measured by Doppler echocardiography, an increased serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, and pulmonary hypertension (PH) diagnosed by right heart catheterization (RHC) are independent risk factors for mortality. METHODS: A multidisciplinary committee was formed by clinician-investigators experienced in the management of patients with PH and/or SCD. Clinically important questions were posed, related evidence was appraised, and questions were answered with evidence-based recommendations. Target audiences include all clinicians who take care of patients with SCD. RESULTS: Mortality risk stratification guides decision making. An increased risk for mortality is defined as a TRV equal to or greater than 2.5 m/second, an NT-pro-BNP level equal to or greater than 160 pg/ml, or RHC-confirmed PH. For patients identified as having increased mortality risk, we make a strong recommendation for hydroxyurea as first-line therapy and a weak recommendation for chronic transfusions as an alternative therapy. For all patients with SCD with elevated TRV alone or elevated NT-pro-BNP alone, and for patients with SCD with RHC-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance, we make a strong recommendation against PAH-specific therapy. However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, we make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy. CONCLUSIONS: Evidence-based recommendations for the management of patients with SCD with increased mortality risk are provided, but will require frequent reassessment and updating.

Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models.

RATIONALE: Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "off-target" effect of enhancing the enzymatic activity of ACE2 in vitro. OBJECTIVES: To evaluate the pharmacological actions of DIZE in experimental models of PH. METHODS: PH was induced in male Sprague Dawley rats by monocrotaline, hypoxia, or bleomycin challenge. Subsets of animals were simultaneously treated with DIZE. In a separate set of experiments, DIZE was administered after 3 weeks of PH induction to determine whether the drug could reverse PH. MEASUREMENTS AND MAIN RESULTS: DIZE treatment significantly prevented the development of PH in all of the animal models studied. The protective effects were associated with an increase in the vasoprotective axis of the lung renin-angiotensin system, decreased inflammatory cytokines, improved pulmonary vasoreactivity, and enhanced cardiac function. These beneficial effects were abolished by C-16, an ACE2 inhibitor. Initiation of DIZE treatment after the induction of PH arrested disease progression. Endothelial dysfunction represents a hallmark of PH pathophysiology, and growing evidence suggests that bone marrow-derived angiogenic progenitor cells contribute to endothelial homeostasis. We observed that angiogenic progenitor cells derived from the bone marrow of monocrotaline-challenged rats were dysfunctional and were repaired by DIZE treatment. Likewise, angiogenic progenitor cells isolated from patients with PH exhibited diminished migratory capacity toward the key chemoattractant stromal-derived factor 1α, which was corrected by in vitro DIZE treatment. CONCLUSIONS: Our results identify a therapeutic potential of DIZE in PH therapy.

Hypoxia-induced endothelial CX3CL1 triggers lung smooth muscle cell phenotypic switching and proliferative expansion.

Distal arterioles with limited smooth muscles help maintain the high blood flow and low pressure in the lung circulation. Chronic hypoxia induces lung distal vessel muscularization. However, the molecular events that trigger alveolar hypoxia-induced peripheral endothelium modulation of vessel wall smooth muscle cell (SMC) proliferation and filling of nonmuscular areas are unclear. Here, we investigated the role of CX3CL1/CX3CR1 system in endothelial-SMC cross talk in response to hypoxia. Human lung microvascular endothelial cells responded to alveolar oxygen deficiency by overproduction of the chemokine CX3CL1. The CX3CL1 receptor CX3CR1 is expressed by SMCs that are adjacent to the distal endothelium. Hypoxic release of endothelial CX3CL1 induced SMC phenotypic switching from the contractile to the proliferative state. Inhibition of CX3CR1 prevented CX3CL1 stimulation of SMC proliferation and monolayer expansion. Furthermore, CX3CR1 deficiency attenuated spiral muscle expansion, distal vessel muscularization, and pressure elevation in response to hypoxia. Our findings indicate that the capillary endothelium relies on the CX3CL1-CX3CR1 axis to sense alveolar hypoxia and promote peripheral vessel muscularization. These results have clinical significance in the development of novel therapeutics that target mechanisms of distal arterial remodeling associated with pulmonary hypertension induced by oxygen deficiency that is present in people living at high altitudes and patients with obstructive lung diseases.

Pulmonary arterial hypertension: classification and therapy with a focus on prostaglandin analogs.

Pulmonary arterial hypertension, part of the larger spectrum of disorders causing pulmonary hypertension, is a complex and progressive disease of multiple etiologies that ultimately leads to vascular remodeling, right-sided heart failure, and death. Advances in treatment over the past 15 to 20 years have dramatically reduced the morbidity and mortality of the disease, but often have significant drawbacks. Of the more recently approved therapies, the prostaglandin analogs have been shown to have the greatest therapeutic benefit but are also the most difficult to administer, many being given as continuous intravenous infusions in the ambulatory setting. After a case presentation highlighting some of the challenges that accompany treatment with these agents, this article reviews the diagnosis and classification of pulmonary hypertension and pulmonary arterial hypertension and gives a brief overview of the various other pharmacologic agents used in its treatment. A more comprehensive review of the biochemistry of prostaglandins and the pharmacology and clinical use of this class of drugs follows. Recommended treatment guidelines are also discussed.

Value of impedance cardiography in patients studied for pulmonary hypertension.

The aim of this study was to evaluate the accuracy and precision of impedance cardiography as a method for noninvasive hemodynamic evaluation of patients with pulmonary hypertension (PH). We performed a prospective and blinded study of patients who underwent right heart catheterization (RHC) for evaluation of known or presumed PH at the University of Florida from August 2009 to March 2010. The cohort consisted of a total of 39 patients (age = 57 ± 14 years, 87% women) with presumed (23%) or confirmed PH (77%) of different etiologies. Patients underwent RHC and impedance cardiography using the PhysioFlow PF-05. The PhysioFlow PF-05 measures cardiac output (CO) and LV end-diastolic volume (LVEDV), among other parameters. The median pulmonary artery pressure was 36 (IQR 26-56) mmHg. The CO (mean ± SD) by thermodilution (CO-T) and by impedance cardiography (CO-IC) was 5.9 ± 2.2 and 5.6 ± 1.5 L/min, respectively. Bland-Altman analysis of CO-T versus CO-IC revealed a mean of 0.3 L/min (95% LoA: -2.2 to +2.8). In patients with PH, the correlation of CO-T and CO-IC had a mean of 0.4 L/min (95% LoA: 2.9 and -2.2). Pulmonary artery occlusion pressure (PAOP) correlated with LVEDV (R (2) = 0.2, p = 0.005). By ROC analysis, EDV ≥ 200 ml had a sensitivity of 53% and a specificity of 86% for PAOP > 15 mmHg (AUC = 0.78). In patients with PH, impedance cardiography had good accuracy and fair precision for CO determination when compared with thermodilution. Impedance cardiography may provide information about the preload status and has the potential to become a cost-effective and noninvasive method for the follow-up of patients with PH.

Effect of balloon inflation volume on pulmonary artery occlusion pressure in patients with and without pulmonary hypertension.

BACKGROUND: Pulmonary artery occlusion pressure (PAOP) is used to differentiate patients with pulmonary hypertension (PH) associated with left-sided heart disease from other etiologies. Technical errors in the measurement of PAOP are common and lead to incorrect classification of the etiology of PH. We investigated the agreement among PAOP measurements obtained from both pulmonary arteries with balloon full (1.5 mL) and half (0.75 mL) inflation in patients undergoing right-sided heart catheterization for suspected PH. METHODS: Thirty-seven patients suspected or known to have PH who underwent right-sided heart catheterization were included. Seventy-six percent had PH (mean pulmonary arterial pressure > 25 mm Hg). The validity of the measurements was assessed by using five preestablished criteria based on hemodynamic, fluoroscopic, and gasometric data. For each patient, the measurement that most likely represented the left atrial pressure was labeled "best PAOP." RESULTS: Seventy percent of all the PAOP measurements met at least four of the five preestablished criteria for validity. In patients with PH (n = 28), the mean ± SE PAOP was 23.1 ± 2 and 19.1 ± 2 mm Hg for balloon full and half inflation, respectively, in the right pulmonary artery and 23.54 ± 2 and 19.07 ± 2 mm Hg for balloon full and half inflation, respectively, in the left pulmonary artery (P = .05). Bland-Altman analysis revealed lower bias and narrower limits of agreement with balloon half inflation. Wedge angiography showed that some balloon inflations failed to occlude upstream flow, whereas others had collateral vessels draining after the occlusion. CONCLUSIONS: PAOP can be falsely elevated in patients with PH according to the balloon inflation volume. Balloon half inflation was safe and correlated with higher precision and lower bias in the PAOP measurements.

Prevalence of pulmonary hypertension in end-stage cystic fibrosis and correlation with survival.

BACKGROUND: Limited information is available about the prevalence of pulmonary hypertension diagnosed by right heart catheterization (RHC) in patients with cystic fibrosis being evaluated for lung transplantation. It is unclear whether there are factors that can predict the presence of pulmonary hypertension and whether the presence of pulmonary hypertension influences patient outcomes. METHODS: The study included 57 unique and consecutive adult patients (33 women) with cystic fibrosis who underwent lung transplant evaluation at the University of Florida. RESULTS: The average age at evaluation was 31.8 +/- 10 years. All patients were in New York Heart Association class III. The median (interquartile range) of mean pulmonary artery pressure (PAP) was 26 (24-30) mm Hg. Thirty-six patients (63.2%) had pulmonary hypertension (mean PAP >or= 25 mm Hg) and had a significantly higher degree of hypoxemia and oxygen requirements. Echocardiography evidenced limitations for the diagnosis of pulmonary hypertension. The 5-year mortality rate was similar in patients with or without pulmonary hypertension; however, it was higher in 7 patients identified by cluster analysis and in patients with a left ventricular ejection fraction < 55%. CONCLUSIONS: More than half of our patients with cystic fibrosis and advanced lung disease have elevation of PAP, usually of mild degree. A lower left ventricular ejection fraction, but not the presence of pulmonary hypertension, was associated with worse outcomes.

Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies.

Doppler-defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD-PH, two randomized, double-blind, placebo-controlled, 16-week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET-1 and -2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6-min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET-1 at baseline, 6MWD correlated with cardiac output (CO; P = 0.006) with non-significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0.07) and between 6MWD and right atrial pressure (P = 0.08). In ASSET-2 at baseline, there was a non-significant correlation between 6MWD and CO (P = 0.06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non-significant increases in CO were observed with bosentan compared to placebo. Similarly, non-significant decreases in PVR were observed with bosentan. Limited data in SCD-PH suggest that a low 6MWD predicts a low CO. Standard-dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.

Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) encompasses a number of diseases responsible for a specific set of hemodynamic findings during right heart catheterization. During initial workup, pulmonary vasodilator testing is performed. A positive acute pulmonary vasodilator test predicts better survival and response to calcium channel blocker (CCB) therapy. There is lack of consensus on the preferred agent for determining acute pulmonary vasoreactivity. The ACCP guidelines and the 4(th) World Symposium on Pulmonary Hypertension support the use of intravenous epoprostenol or nitric oxide (NO) as the preferred agents for pulmonary vasodilator testing. A decrease in the mean pulmonary artery pressure by at least 10 mmHg to reach an absolute value of 40 mmHg or less without a decrease in cardiac output is currently considered a positive pulmonary vasodilator test. A positive test by the current recommended criteria is observed in about 10-15% of patients with idiopathic PAH. Approximately half of these patients will experience long-term benefits with CCBs. A positive test may select patients with an earlier or less aggressive form of disease, which may carry a better prognosis. A positive vasodilator test is observed very infrequently in patients with pulmonary arterial hypertension other than idiopathic PAH or anorexigen associated PAH. This article reviews the literature regarding pulmonary vasodilator testing and use of CCB therapy in patients with PAH, while identifying the gaps in knowledge concerning this diagnostic procedure.

A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension is a chronic, progressive disease characterized by elevation of pulmonary artery pressure and pulmonary vascular resistance that ultimately results in right ventricular failure and death. Multiple mechanisms are involved in the pathogenesis of pulmonary arterial hypertension, including prostacyclin, endothelin-1, and nitric oxide pathways amongst others. The first agent to be approved for the treatment of pulmonary arterial hypertension was synthetic prostacyclin (epoprostenol), followed by prostaglandin analogs (iloprost, treprostinil, and beraprost [Japan and Korea]), which act on prostaglandin receptors. This article reviews the physiology and pathophysiology of prostanoids, summarizes key clinical studies of prostaglandin analogs for the treatment of pulmonary arterial hypertension, and discusses important pharmacokinetic and pharmacodynamic distinctions between the various prostaglandin analogs. Different prostaglandin analogs have disparate binding affinities for the various prostaglandin receptors and different G-protein-coupled receptor interactions, which may result in varying clinical efficacy and safety depending on the target tissue. Differences in formulation, route of administration, effectiveness, and safety may all play a role in deciding which prostaglandin analog to prescribe for an individual patient. Head-to-head studies will be needed to confirm differences in efficacy and safety for the various prostaglandin analogs.

Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-beta1 in vitro.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells (PMC) are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor (TGF)-beta1, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of TGF-beta1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by TGF-beta1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-beta1 and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin (alpha-SMA), fibroblast specific protein-1 (FSP-1), and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to TGF-beta1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.

Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease.

RATIONALE: The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear. OBJECTIVES: A second year of follow-up was performed to determine if these effects persisted after stopping treatment. METHODS: A detailed analysis of data obtained over the two years of the study was performed. MEASUREMENTS AND MAIN RESULTS: Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire-Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon. CONCLUSIONS: One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: results from the scleroderma lung study.

OBJECTIVE: To assess the impact of cyclophosphamide (CYC) on the health-related quality of life (HRQOL) of patients with scleroderma after 12 months of treatment. METHODS: One hundred fifty-eight subjects participated in the Scleroderma Lung Study, with 79 each randomized to CYC and placebo arms. The study evaluated the results of 3 measures of health status: the Short Form 36 (SF-36), the Health Assessment Questionnaire (HAQ) disability index (DI), and Mahler's dyspnea index, and the results of 1 preference-based measure, the SF-6D. The differences in the HRQOL between the 2 groups at 12 months were calculated using a linear mixed model. Responsiveness was evaluated using the effect size. The proportion of subjects in each treatment group whose scores improved at least as much as or more than the minimum clinically important difference (MCID) in HRQOL measures was assessed. RESULTS: After adjustment for baseline scores, differences in the HAQ DI, SF-36 role physical, general health, vitality, role emotional, mental health scales, and SF-36 mental component summary (MCS) score were statistically significant for CYC versus placebo (P < 0.05). Effect sizes were negligible (<0.20) for all of the scales of the SF-36, HAQ DI, and SF-6D at 12 months. In contrast, a higher proportion of patients who received CYC achieved the MCID compared with placebo in the HAQ DI score (30.9% versus 14.8%), transitional dyspnea index score (46.4% versus 12.7%), SF-36 MCS score (33.3% versus 18.5%), and SF-6D score (21.3% versus 3.8%). CONCLUSION: One year of treatment with CYC leads to an improvement in HRQOL in patients with scleroderma lung disease.

Cyclophosphamide versus placebo in scleroderma lung disease.

BACKGROUND: We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease. METHODS: At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC. RESULTS: Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant. CONCLUSIONS: One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.

Correlation of the degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis: results from the Scleroderma Lung Study.

OBJECTIVE: To determine whether baseline self-assessment measures of health status and physiologic indices of disease severity in alveolitis-positive patients with systemic sclerosis (SSc) correlate with the severity of their dyspnea, and to quantify functional impairment in patients with scleroderma lung disease and compare it with that in patients with chronic obstructive pulmonary disease (COPD). METHODS: SSc patients (n = 138) with diffuse (n = 81) or limited (n = 57) cutaneous disease and active alveolitis (determined by bronchoalveolar lavage and/or high-resolution computed tomography) who participated in the National Heart, Lung, and Blood Institute-sponsored, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial of oral cyclophosphamide for treatment of SSc-associated interstitial lung disease were evaluated. Pearson's univariate correlations were determined between the Short Form 36 (SF-36) physical component summary (PCS) and mental component summary (MCS) scales, functional questionnaires, and physiologic parameters of breathing (forced vital capacity [FVC] and single-breath diffusing capacity for carbon monoxide [DLCO]). Student's t-test was used to compare subgroups. Scores from 2 instruments for self-assessment of breathlessness, Mahler's baseline dyspnea index (BDI) and a visual analog scale (VAS) for breathing, were divided at the median. Values for the DLCO and FVC (% predicted) were divided based on the American Thoracic Society guidelines for mild (>70% of predicted), moderate (50-70% of predicted), and severe (<50% of predicted) physiologic impairment. RESULTS: Scores on the BDI and VAS for breathing were highly correlated (r = -0.61). The PCS and MCS were able to differentiate patients with more breathlessness (measured by BDI and VAS for breathing) and more abnormal physiologic measures (FVC and DLCO). In SSc patients with alveolitis, all 8 domains of the SF-36 were significantly impaired as compared with the healthy population and were similar to those reported by patients with COPD. CONCLUSION: The SF-36 was able to discriminate between scleroderma lung disease patients with more severe and less severe breathlessness, the primary symptom of active alveolitis. The SF-36 complements the BDI and VAS scores for breathing in scleroderma lung disease and is variably correlated with results of pulmonary function tests, suggesting that the SF-36 should be included as an outcome measure in intervention trials in this population.