Exhaled NO and Oxidative Stress in Systemic Sclerosis Pulmonary Hypertension

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Project Summary/Abstract This research application proposes to conduct an ancillary study to a clinical trial planned soon as a component of the recently funded, multi-disciplinary Specialized Center of Clinically Oriented Research (SCCOR) in Pulmonary Hypertension at our institution, which has as its focus, Pulmonary Arterial Hypertension Associated with Systemic Sclerosis (PAH-SSc). This study seeks to develop and validate exhaled nitric oxide (NO) and urine isoprostanes as clinically relevant biomarkers in PAH-SSc. Excessive oxidative stress with consequent impairment in NO, may be critical events in the development of PAH- SSc that can be targeted by current PAH therapies. We hypothesize that these markers will: 1) predict the subsequent response to PAH therapy and 2) serve as surrogate therapeutic end-points to clinically relevant outcomes. In the parent clinical trial, treatment na¿ve PAH-SSc patients (N=75) will be enrolled in a randomized study of bosentan, sildenafil or the combination of both for 16-weeks. These agents are currently the most widely employed therapies for this condition. Detailed clinical, functional and hemodynamic assessments will be conducted as part of the parent trial. This ancillary study will obtain exhaled NO and urine F2-isoprostane (a marker of oxidative stress) measurements at baseline and after therapy. In our first aim, baseline measures will be compared with those obtained from SSc patients without lung disease and healthy control subjects. The latter goups will be recruited from two other parent studies that are components of our SCCOR program. In aim 2, baseline biomarker measurements will be correlated with response to therapy. In addition, changes in these indices after 4, 8 and 16 weeks of therapy will be correlated with changes in clinical measures of disease severity after 16 weeks. The long-term objectives of this research are to identify reliable biomarkers in PAH-SSc and advance our understanding of the mechanism(s) of action of medical therapy for this devastating disease. Validation of these measurements may ultimately allow tailoring of therapy to individual patients or identify those who are unlikely to benefit from a certain therapy early, so that a change can be made before clinical deterioration occurs. Subsequent studies could determine if these simple, readily obtained, non-invasive tests prove to be useful in identifying asymptomatic patients with SSc at high-risk for subsequent development of clinically manifest PAH, allowing the potential application of preventative therapies. By providing mechanistic insights, this research may also serve as a basis for the testing of novel therapeutic classes, such as anti-oxidants and/or NO donors.