Project Summary Clinical outcomes for patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) remain poor. Although there have been many advancements in therapeutics for pulmonary arterial hypertension (PAH), patients with SSc-PH, conventionally classified as Group I PAH, continue to have increased mortality compared to patients with idiopathic PAH. Hence, there is an unmet need to understand why this occurs. In this work, we determine whether left ventricular (LV) dysfunction plays a role in contributing to elevated pulmonary pressures in this patient population. The results from these findings will indicate that: 1) There may be a greater prevalence of cardiac involvement than presumed in this population; and/or 2) LV dysfunction is a consequence of PAH from increased pulmonary arterial pressures and resultant right ventricular overload that impairs LV systolic contractility. Using the Scleroderma Center of Research Translation (CORT) database, a clinical registry of patients with SSc followed within the Scleroderma program since 2002, the specific aims of this proposal are to: evaluate the longitudinal changes in subclinical LV strain in SSc patients (Aim 1); and, identify and characterize clinical phenotypes in SSc-PH using LV strain by cluster analysis (Aim 2). This proposed work will test our hypothesis that patients with SSc-PH will exhibit preexisting LV dysfunction prior to diagnosis of SSc- PH and that the rate of reduction of LV strain will be greater in patients with SSc-PH in comparison to those who do not develop SSc-PH. We also hypothesize that patients with a clinical phenotype of SSc- PH associated with LV dysfunction will have poorer 3-year survival rates in comparison to patients without evidence of LV dysfunction. The F32 award, with the didactics, mentorship, and research experience it affords, is a critical step on my path to becoming an independent physician-scientist specialized in pulmonary vascular clinical research. Results from Aims 1 and 2 will raise the notion that patients with SSc-PH require a different approach to therapy and will inform a subsequent K award focusing on: 1) The role of LV dysfunction in assessing response to PAH therapy; 2) The role of LV dysfunction in risk prognostication in SSc-PH; and potentially, 3) The rationale for novel therapies to treat and improve care of patients with SSc-PH. This proposed work will align with the following goals of the National Heart, Lung, and Blood Institute in: 1) Identifying factors that account for individual differences in pathobiology and in responses to treatments; and, 2) Developing and optimizing novel diagnostic and therapeutic strategies to prevent, treat, and cure heart, lung, blood, and sleep diseases.