Heart failure (HF) is a leading cause of morbidity, mortality and escalating health care costs within the VA. The type of HF that is increasing disproportionately is HF with a preserved ejection fraction (HFpEF), commonly caused by hypertension and left ventricular (LV) pressure overload. An estimated 10% to 20% of hypertensive patients have resistant hypertension (RHTN), defined as having controlled or uncontrolled blood pressure with the use of ≥ 3 medications that includes a diuretic. We previously reported significant LV hypertrophy and diastolic dysfunction with normal systolic function in persons with RHTN. Hypertension among Black adults in the US has one of the highest prevalence rates in the world and is related to adverse changes in LV structure and function. Hypertension is an underlying factor in >50% of Black adults with HF and is the strongest risk factor for HF in that population.8 Black adults have a 50% increased incidence of HF, due in large part to the greater prevalence and severity of hypertension, and HF occurs 8 years earlier in Black adults as compared with Whites. Although Black adults have the highest death rate for HF, they are consistently underrepresented in clinical trials. The greater HF burden among Black adults calls for further work to discover effective preventive and therapeutic strategies for this higher-risk population. The greater HF burden among Black adults calls for further work to discover effective preventive and therapeutic strategies for this higher-risk population. The long-term goal of this project is to develop an effective strategy to improve the health of African American Veterans with HFpEF. We have recently reported increased plasma xanthine oxidase (XO) activity and mtDNA damage associated molecular products (DAMPs) levels in Black adults with RHTN, compared with White adults with RHTN. This supports the general consensus that oxidative stress is higher in black adults. XO oxidizes hypoxanthine and xanthine to generate hydrogen peroxide and superoxide as a byproduct. These products damage mitochondria leading to bioenergetic dysfunction and further amplification of oxidant generation and production of mtDNA DAMPs. mtDNA DAMPs are potent activators of the innate immune response through several pathways including activation of TLR (toll-like receptor) with promotion of pro- inflammatory cytokine release. We have shown diastolic blood pressure (r=0.876, p<.001), LV end-diastolic mass index (r=0.503, p=0.012), fractional shortening (r=-0.546, p=0.006), wall thickness (r=0.428, p=0.001), mid-wall radius to wall thickness ratio (r=0.354, p=0.008), and early diastolic filling rate (r=-0.422, p=0.04) were related to XO activity at six months among the Blacks but not White RHTN patients. Given the higher level of XO activity and mtDNA DAMPs in blacks, we hypothesize that inhibition of XO improves LV diastolic function in Black African Americans with RHTN. We will address this hypothesis in the followin...