Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right heart failure and death. While new therapies targeting the pulmonary vasculature in PAH have improved quality of life, functional capacity, and survival in patients with idiopathic PAH (IPAH), these therapies have had limited impact in PAH related to scleroderma (PAH-SSc). The reasons for these differences in response to therapy are unclear. Despite a preponderance of evidence supporting a central role of neurohormonal dysfunction in heart failure due to left heart disease, little attention has been paid to its potential role in the pathophysiology of PAH and right heart failure, particularly with respect to PAH-SSc. Patients with scleroderma have underlying autonomic dysfunction which may predispose them to a more rapidly progressive clinical course to right heart failure and death. Further, the higher prevalence of left heart disease in PAH-SSc compared to IPAH may influence neurohormonal function. We hypothesize that neurohormonal activation (NHA) in PAH-SSc explains differences in response to therapy and decreased survival in this group compared to IPAH patients. Therefore, we propose a prospective cohort study of patients with PAH-SSc and IPAH to address three specific aims (SA). In SA'#1, we will define whether NHA differs between IPAH and PAH-SSc by 1) measuring serum markers ofthe neurohormonal axis;2) measuring heart rate variability;and 3) assessing NHA gene expression profiles of right ventricular biopsies. In SA#2, we will determine whether differences in NHA between these two groups predict hospitalization and risk of death. In SA#3, we will test for association of select haplotypes of genes relevant to the neurohormonal axis, and previously shown to have clinical importance in left heart failure, with PAH-type (IPAH vs. PAH-SSc) and their relationship to survival. Completion ofthe proposed research, along with complementary training and mentorship within an outstanding and supportive environment for clinical research, will ensure that the principal investigator gains in-depth exposure to clinical research design, conduct, and analysis. These experiences will allow the principal investigator to develop into an individual capable of pursuing a successful career as an independent investigator in academic medicine.
;Survival in PAH related scleroderma is worse than in IPAH. The reasons for this survival difference are unclear but may be related to an exaggerated response to stress on the heart. Previous studies of patients with heart failure have shown that the response to stress on the heart determines disease severity and survival and may be modified with specific medications. We believe similar mechanisms are involved in PAH related to scleroderma mav explain their poor survival and can potentially be modified bv theraov.
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