# Genetic variation in xanthine oxidase and heart failure preserved ejection fraction

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2024 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10701327
- **Project number:** 1I01BX005996-01A2
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Louis J. Dell'Italia
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701327

## Citation

> US National Institutes of Health, RePORTER application 10701327, Genetic variation in xanthine oxidase and heart failure preserved ejection fraction (1I01BX005996-01A2). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10701327. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*