Heart failure (HF) with preserved left ventricular ejection fraction (HFpEF) caused by hypertension is a leading cause of morbidity and mortality and escalating health care costs. As opposed to heart failure with reduced ejection fraction (HFrEF), the heart cannot properly fill, resulting in left ventricular diastolic dysfunction and heart failure symptoms. In clinical trials, pharmacological strategies that mitigate HF progression in HFrEF patients are not as effective in HFpEF patients, rendering HFpEF patients susceptible to cardiac events including hospital readmission. About 10-20% of patients with hypertension have treatment resistant hypertension. There is a phenotype of left ventricular dysfunction in resistant hypertension. Importantly HFpEF still occurs even when blood pressure is controlled. Treatment options for HFpEF are largely limited to decongestion by diuretics. To address the clinical need this project will investigate in an innovative way a potential new target, xanthine oxidoreductase (XOR), which may reveal a new treatment approach for treating and preventing HFpEF. XOR produces urate with concomitant production of damaging reactive oxygen species. Of direct relevance to this proposal increased XOR in the heart cardiomyocyte causes a breakdown of myofibrils (contractile units in the sarcomere) and decrease in calcium sensitivity, resulting in left ventricular dysfunction. We have reported increased XOR activity in the left ventricle of patients with resistant hypertension, with a greater increase in African Americans. The gene encoding XOR (xanthine dehydrogenase, XDH) is genetically associated with urate levels by genome-wide association study and we have preliminary data for association of the same genetic signal with gout. These variants regulate expression of XOR, indicating functional genetic variant(s) that can be used as a basis to develop a causal inference instrument for the effect of XOR activity on HFpEF and risk factors resistant hypertension and progression of left ventricular diastolic dysfunction. We will test the hypothesis that increased XOR activity is causal of HFpEF. We will develop a genetic score for XOR activity and test for a possible causal role in HFpEF by Mendelian randomization in White and African American cohorts in the MVP data. In secondary analysis we will test the score for a possible causal role in resistant hypertension and LV dysfunction. The XOR activity score will be developed in Aim 1. This will be done in two sub-aims. Aim 1a. Test XDH variants that associate with expression of XDH for association with plasma XOR activity in a newly recruited cohort from the VA with replication in an existing cohort from the Alabama Genomic Health Initiative; Aim 1b. Scan the genome outside of the XDH gene locus for other genetic variants that control XOR activity. In Aim 2 the genetic variants identified in Aim 1 will be combined into an XOR activity score and in the MVP cohort tested for a possible c...