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Principal Investigator: Louis J. Dell'Italia
Organization: BIRMINGHAM VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
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 causal role in HFpEF in the primary analysis using the Mendelian randomization
technique, and in secondary analysis a possible causal role in resistant hypertension and left ventricular
diastolic dysfunction. Mediation through resistant hypertension and left ventricular diastolic dysfunction will
be tested. The influence of XOR inhibition (allopurinol and febuxostat) will be evaluated by testing for non-
additive interaction.
Our findings may provide a premise for clinical trial of XOR inhibition in prevention of HFpEF.
Terms: <Active Oxygen><Address><African American><African American group><African American individual><African American people><African American population><African Americans><Afro American><Afroamerican><Alabama><Alleles><Allelomorphs><Allopurinol><Blood Plasma><Blood Pressure><Blood Serum><Caffeine><Calcium><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Causality><Cell Communication and Signaling><Cell Signaling><Clinical><Clinical Research><Clinical Study><Clinical Trials><Coffee><Consumption><Data><Development><Diuretics><Dysfunction><EFRAC><Ejection Fraction><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Etiology><Event><Functional disorder><GWA study><GWAS><Gene variant><Genes><Genetic><Genetic Diversity><Genetic Variation><Genome Scan><Genomics><Gout><Health><Health Care Costs><Health Costs><Healthcare Costs><Heart><Heart Muscle Cells><Heart failure><Heart myocyte><Hypertension><Hypoxanthine Dehydrogenase><Hypoxanthine Oxidase><Hypoxanthine-Xanthine Oxidase><Hypoxanthines><Individual><Intracellular Communication and Signaling><LV Mass><LVEF><Left><Left Ventricles><Left Ventricular Dysfunction><Left Ventricular Ejection Fraction><Left Ventricular Mass><Left ventricular structure><Mediating><Mediation><Medical><Mendelian randomization><Morbidity><Morbidity - disease rate><Myofibrils><NAD+ oxidoreductase Xanthine><Negotiating><Negotiation><Other Genetics><Outcome><Oxygen Radicals><Participant><Patients><Phenotype><Physiopathology><Plasma><Plasma Serum><Predisposition><Prevention><Preventive><Pro-Oxidants><Production><Proxy><Purine Hydroxylase I><Purine-Xanthine Oxidase><Race><Races><Reactive Oxygen Species><Reporting><Research Design><Resistant Hypertension><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Role><Sampling><Sarcomeres><Serum><Sigapurol><Signal Transduction><Signal Transduction Systems><Signaling><Study Type><Susceptibility><Symptoms><System><Techniques><Testing><Translating><Urate><Variant><Variation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Ventricular><Veterans><Woman><Work><XDH><XDH gene><Xanthine Dehydrogenase><Xanthine Dehydrogenase Gene><Xanthine Oxidase><Xanthine Oxidoreductase><allele variant><allelic variant><biological signal transduction><cardiac failure><cardiomyocyte><caucasian American><causation><clinical practice><co-morbid><co-morbidity><cohort><comorbidity><developmental><disease causation><epidemiologic investigation><epidemiology study><febuxostat><gene locus><genetic locus><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome-wide scan><genomewide association scan><genomewide association studies><genomewide association study><genomewide scan><genomic location><genomic locus><genomic variant><heart failure and reduced ejection fraction><heart failure with reduced ejection fraction><high blood pressure><hospital re-admission><hospital readmission><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><innovate><innovation><innovative><instrument><left ventricle abnormality><men><mortality><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pharmacologic><preservation><prevent><preventing><programs><racial><racial background><racial origin><re-admission><re-hospitalization><readmission><recruit><rehospitalization><secondary analysis><social role><study design><white American><whole genome association analysis><whole genome association studies><whole genome association study><whole-genome scan>