Chronic exposure to hypobaric hypoxia (HH) causes pulmonary hypertension (PH) and right ventricular (RV) dysfunction, a strong predictor of survival in a variety of clinical contexts. Inflammatory-fibrotic remodeling underlies PH-induced RV dysfunction, a process regulated in part by cardiac fibroblasts (Cfib). In response to insult, Cfib undergo phenotypic changes including hypersecretion of bioactive molecules which may contribute to ventricular dysfunction. We hypothesized that persistent changes in the activated Cfib phenotype would be mediated through DNA methylation and that secretion of signals from the activated Cfib would contribute to cardiomyocyte dysfunction. We tested this hypothesis using RV Cfib derived from the neonatal calf exposed to HH- a novel large animal model with significant resonance with human disease. HH exposure resulted in an epigenetically modified pro-inflammatory Cfib characterized by global DNA hypomethylation, elevated IL-1β signaling, and activation of a myofibroblast phenotype. IL-1β treatment of control Cfib also elicited DNA hypomethylation and phenotype conversion, albeit less robustly than Cfib derived from the HH-exposed RV. Treatment of adult rat ventricular myocytes (ARVM) with conditioned media from HH-derived Cfib caused dedifferentiation of ARVM to a neonatal-like phenotype characterized by activation of the fetal gene program. Immunodepletion of IL-1β from HH conditioned media attenuated expression of fetal genes and myocyte dedifferentiation. However, IL-1β treatment alone was not sufficient to cause dedifferentiation and fetal gene expression, suggesting other secreted (inflammatory) factors contribute to myocyte disarray and dysfunction. Together, these data suggest a key role of the epigenetically modified activated Cfib in the pathogenesis of PH-induced RV dysfunction, mediated in part by IL-1β signaling. Ongoing investigations will identify other pathways of Cfib-mediated ventricular dysfunction to facilitate manipulation of the fibroblast for therapeutic benefit in right heart disease.