A Randomized, Double-Blind, Placebo-Controlled Study of Pulsed, Inhaled Nitric Oxide in Subjects at Risk of Pulmonary Hypertension Associated With Pulmonary Fibrosis.

BACKGROUND: The interstitial lung diseases include a variety of disorders, many of which are characterized by fibrotic changes (fILD). Of the fILDs, Idiopathic pulmonary fibrosis is the most common. Pulmonary hypertension (PH) frequently complicates fILD and is associated with impaired functional capability, lower physical activity, and significantly reduced life expectancy. There is no proven treatment for patients with fILD-PH. We report results from the first cohort of a phase 2b/3 trial with pulsed inhaled nitric oxide (iNO) in patients with fILD-PH. METHODS: Subjects in cohort 1 were randomized to iNO 30 µg/kg ideal body weight/h (iNO30) or placebo for 8 weeks of blinded treatment; subjects then transitioned to open-label extension (OLE) on iNO30 followed by dose escalation to iNO45 then iNO75. Activity monitoring was used to assess changes in daily activity. Safety and efficacy were evaluated. RESULTS: Twenty-three patients were randomized to iNO30 and 18 to placebo. During blinded treatment, iNO30 subjects showed an average improvement in moderate/vigorous physical activity (MVPA) and remained stable in overall activity. Placebo subjects showed an average drop of 26% in MVPA and a 12% drop in overall activity. The iNO group had an improvement in oxygen saturation. During OLE, subjects maintained their activity levels including placebo subjects who transitioned from a decline to a maintenance in all activity parameters. Inhaled nitric oxide at all doses (30, 45, and 75) was safe and well tolerated. CONCLUSIONS: Treatment with iNO30 demonstrated clinically and statistically significant benefit in MVPA and clinically significant benefit in overall activity. In the OLE, higher doses of iNO were also safe and well tolerated while showing maintenance in activity parameters.

Negative effects of pretransplant body mass index on physical health-related quality of life after lung transplant.

BACKGROUND: Although current national data show improved graft and patient survival following lung transplant, the effects of several modifiable preexisting comorbid conditions on health-related quality of life after transplant have not been evaluated. This study examines the effects of 3 comorbid conditions present before lung transplant (reduced bone density, diabetes mellitus, and elevated body mass index) on health-related quality of life after lung transplant. METHODS: The Short Form 36 Health Survey was completed by 92 adult recipients at various times after lung transplant (mean, 41 months; range, 1-127 months). Multiple linear regression models that controlled for underlying disease, chronic rejection, and time after transplant tested the independent effects of the 3 pretransplant conditions on posttransplant health-related quality of life. RESULTS: The effects of pretransplant reduced bone density and diabetes mellitus were not statistically significant in these models. However, pretransplant body mass index had a significant negative effect (ß = -.29, P = .007) on posttransplant physical health-related quality of life. Additionally, overweight status and obesity exerted comparable independent negative effects (P = .01 and P = .03, respectively) on the physical function scale of the Short-Form 36 Health Survey compared with persons who were underweight or normal weight before transplant. CONCLUSIONS: Reevaluation of elevated body mass index before transplant as a risk for reduced physical quality of life after lung transplant should be considered.

Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance.

BACKGROUND: While BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease. This finding suggests that modifier genes contribute to FPAH clinical expression. Since modifiers are likely to be common alleles, this problem is not tractable by traditional genetic approaches. Furthermore, examination of gene expression is complicated by confounding effects attributable to drugs and the disease process itself. METHODS: To resolve these problems, B-cells were isolated, EBV-immortalized, and cultured from familial PAH patients with BMPR2 mutations, mutation positive but disease-free family members, and family members without mutation. This allows examination of differences in gene expression without drug or disease-related effects. These differences were assayed by Affymetrix array, with follow-up by quantitative RT-PCR and additional statistical analyses. RESULTS: By gene array, we found consistent alterations in multiple pathways with known relationship to PAH, including actin organization, immune function, calcium balance, growth, and apoptosis. Selected genes were verified by quantitative RT-PCR using a larger sample set. One of these, CYP1B1, had tenfold lower expression than control groups in female but not male PAH patients. Analysis of overrepresented gene ontology groups suggests that risk of disease correlates with alterations in pathways more strongly than with any specific gene within those pathways. CONCLUSION: Disease status in BMPR2 mutation carriers was correlated with alterations in proliferation, GTP signaling, and stress response pathway expression. The estrogen metabolizing gene CYP1B1 is a strong candidate as a modifier gene in female PAH patients.