Introduction: The compensatory stage in right ventricle hypertrophy (RVH) in pulmonary arterial hypertension (PAH) is much shorter than in left ventricle hypertrophy (LVH) in systemic hypertension. Between 2 patients with the same degree of PAH one may have a much shorter compensated RVH (cRVH) stage than the other. The cardiac myofibroblasts (CMF) may contribute to these differences. Their ability to contract (stiffening), produce collagen and promote inflammation contributes to heart failure. Decreased mitochondrial calcium (mCa++) promotes CMF differentiation (from cardiac fibroblasts). Methylation of the mCa++ Uptake 1 (MICU1) and lack of UCP2 (uncoupling protein 2, a component of the mCa++ uniporter complex) activate CMF in the LV. Hypothesis: RV CMF are major contributors to RV failure in PAH, and loss of CMF-UCP2 promotes myofibroblast activation and RV decompensation. Methods: In a rat PAH model (Monocrotaline-PAH), we measured the RV pressure from isolated perfused hearts and sarcomere shortening from isolated RV cardiomyocytes. In a cohort (n=25) of patients with pulmonary hypertension that had been treated with the same protocol for years and controlled for age/sex/duration of disease, the correlation between UCP2 loss-of-function SNPs and RV function was measured. Results: In isolated hearts, RV pressure is lower in decompensated RVH (dRVH) compared to normal RV, but in vitro there is no difference in cardiomyocyte sarcomere shortening between the two groups, pointing to potential detrimental role of RV CMF rather than contractile failure of RV cardiomyocytes. dRVH has much more CMF compared to normal RV. CMF from dRVH have increased MICU1 methylation and decreased UCP2 levels compared to normal RV fibroblasts. PAH patients with homozygotes for UCP2 SNPs have worse RV function compared to heterozygote or wild-type, despite similar PA pressures. Conclusions: Our preliminary work suggests that RV CMF rather than RV cardiomyocytes may drive RV decompensation independent of RV afterload in PAH patients and this may be predicted by UCP2 SNPs that are relatively frequent in the population and have been shown to be associated with PAH outcomes (10-year survival, time to transplantation).