Heart failure with preserved ejection fraction (HFpEF) is a major driver of morbidity and mortality among the aging population and is a rapidly growing public health problem. However, there are no specific therapies for HFpEF and the negative results of a growing number of clinical trials are thought to be due, in large part, to substantial clinical heterogeneity of HFpEF. This has led to a call for deeper phenotyping to better target therapeutic clinical trials. One specific HFpEF phenotype with particularly poor outcomes is pulmonary hypertension (PH), which can result from chronic congestion of the pulmonary vasculature in HFpEF. Altered glucose metabolism has also been implicated in both HFpEF and PH, as well as specifically the PH-HFpEF phenotype. Our preliminary data on the cardiopulmonary physiology of PH-HFpEF from a recent phase II clinical trial suggests abnormal aging of the pulmonary vasculature with a steep decline in its compliance. We found that PH-HFpEF patients are typically in their 60's with a high prevalence of metabolic syndrome characteristics. Further, observational research suggests metformin may be associated with improved outcomes in heart failure. Additionally, we have studied the impact of metformin in an obese animal model of PH-HFpEF and shown a reduction in pulmonary pressures associated with increased 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Increased AMKP was associated with a novel finding of upregulated sirtuin-3 (SIRT3) in skeletal muscle, but not in the lung or heart. AMPK regulates glucose uptake in skeletal muscle and is dysregulated in metabolic syndrome, heart failure, and PH. We have found decreased activation of SIRT3 in skeletal muscle biopsies from HFpEF patients and that skeletal muscle activation of SIRT3 drives secretion of the myokine, fibroblast growth factor 21 (FGF21). FGF21 inhibits pulmonary artery smooth muscle cell proliferation and confers systemic benefits on insulin resistance in an AMPK-dependent manner. These lines of evidence together suggest that metformin has significant promise for the specific treatment of PH-HFpEF. We propose a 12-week blinded cross over trial of metformin in PH-HFpEF to improve exercise hemodynamics, functional capacity, and glucose metabolism. This phase II clinical trial will provide detailed phenotyping and physiological data on PH-HFpEF (Aim 1). The primary outcome will be exercise mean pulmonary artery pressure. Secondary endpoints will include functional capacity as assessed by continuous work load exercise testing, activity monitoring by accelerometer, distance walked in 6 minutes, as well as cardiopulmonary hemodynamics (pulmonary artery pressures, resistance, and vascular compliance). Glucose tolerance and insulin sensitivity will be assessed. Skeletal muscle biopsies will be taken to study SIRT3-AMPK signaling, muscle fiber switch, and FGF21-adiponectin secretion (Aim 2). Results from this study will provide valuable i...