Allopurinol Improves Heart Function in African Americans With Resistant Hypertension (RESIST)

African American adults in the United States have the highest prevalence rate of high blood pressure (hypertension) and heart failure in the world. African Americans with treatment resistant hypertension have higher levels of the enzyme - xanthine oxidase compared to Caucasians. This trial will test if administration of the xanthine oxidase inhibitor - Allopurinol (commonly used in the treatment of gout), given over a period of 8 weeks, will improve heart function, exercise ability and quality of life in African American Veterans with resistant hypertension.

Hypertension among African American adults in the United States has one of the highest prevalence rates in the world and is related to adverse changes in left ventricular (LV) structure and function. Hypertension is an underlying factor in greater than 50% of African American adults with heart failure and is the strongest risk factor in that population. African American adults have a 50% increased incidence of heart failure, due in large part due to the greater prevalence and severity of hypertension. Heart failure occurs 8 years earlier in African American adults compared with Caucasians. Further, African American adults with heart failure have worse quality of life and depressive symptoms and have a 5-year mortality rate that is 34% higher than in Caucasians. Although African American adults have the highest death rate for heart failure, they are consistently under-represented in clinical trials. The greater heart failure burden among African Americans calls for further work to discover effective preventive and therapeutic strategies for this higher-risk population with heart failure preserved ejection fraction (HFpEF). An estimated 10-20% of hypertensive patients have resistant hypertension (RHTN), defined as having controlled or uncontrolled blood pressure with the use of 3 or more medications that includes a diuretic. A recent study reported increased plasma xanthine oxidase (XO) activity and mitochondrial DNA damage associated molecular products (mtDAMPs) levels in African American adults with RHTN, compared with Caucasian adults with RHTN. This supports the consensus that oxidative stress is higher in African American adults. Increased xanthine oxidase in heart muscle cells causes a breakdown of muscle structure and a decrease in calcium sensitivity, resulting in left ventricular (LV) dysfunction. A recent study shows that diastolic blood pressure, and other indices of LV diastolic function positively relate to xanthine oxidase activity among African American but not Caucasian RHTN patients. Given the higher level of xanthine oxidase activity and mtDAMPs in African Americans, the purpose of this clinical trial is to test whether blockade with Allopurinol (for 8 weeks) will improve LV diastolic function, exercise capacity and quality of life metrics in 50 African American Veterans with resistant hypertension.

This is an open label unblinded drug pilot study to determine whether Allopurinol improves left ventricular diastolic function, exercise capacity, and quality of life in African American Veterans with resistant hypertension after 8-weeks of treatment.

Subjects will receive Allopurinol (300mg/daily) for 4 weeks. If tolerated, dose will be increased to 600mg/daily for an additional 4 weeks. Subjects will take Allopurinol (300-600mg/daily) for 8 weeks total

Single arm of Allopurinol treatment for 300mg/daily for 4 weeks then increased to 600mg/daily for an additional 4 weeks.

Change from baseline in left ventricular diastolic function index: Normalized peak early diastolic filling rate (E) after 8-weeks of treatment with Allopurinol. (Range 1.5 - 3.0 EDV/sec)

Change in exercise capacity by six minute walk test after 8-weeks of Allopurinol. Timed activity for distance walked (Distance range approximately 400-800m; Further distance = better outcome)

Change in self reported quality of life measures using Kansas City Heart Failure Questionnaire (KCCQ-12) after 8-weeks of Allopurinol. Scale (Minimum - 0 ; Maximum - 100; High score = worse outcome)

Change in self reported quality of life measures using the Quality of Life Medical Outcomes Study Questionnaire (SF 36 QOL) after 8-weeks of Allopurinol. Scale (Minimum - 0; Maximum - 100; High score = worse outcome)

Change from baseline in left ventricular diastolic function index: left ventricular end diastolic volume normalized to body surface area after 8-weeks of treatment with Allopurinol. (Range 40 - 100 mL/m2)

Change from baseline in left ventricular diastolic function index: LV end-diastolic mass indexed to body surface area after 8-weeks of treatment with Allopurinol. (Range: 40-100 grams/m2)

Change from baseline in left ventricular diastolic function index: LV end-diastolic fractional shortening after 8-weeks of treatment with Allopurinol. (Range: 15-80%)

Change from baseline in left ventricular diastolic function index: LV end-diastolic mid-wall radius to wall thickness ratio. Ratio (no units; Range: 1.5-4.0).

Change from baseline in left ventricular diastolic function index: Normalized peak late diastolic filling rate (A) after 8-weeks of treatment with Allopurinol. (Range 1.3 - 4.5 EDV/sec)

Change in systemic levels of xanthine oxidase (range - Xanthine oxidase activity, U/mg protein - Range 0 - 0.1)

Change in systemic levels of mitochondrial DNA damage-associated molecular patterns (range 0-5000 copies/uL)

Change in systemic levels of brain natriuretic peptide (BNP) after 8 weeks of Allopurinol (Scale 0 to > 100 pgmL; Minimum 0; Maximum >100).

Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Veteran African American Resistant hypertension diagnosis (defined as blood pressure greater than 140/90 mmHg at 2 clinic visits despite the use of 3 antihypertensive medications at pharmacologically effective doses) Locale - Birmingham, AL and surrounding areas Exclusion Criteria: History of heart failure Chronic kidney disease (estimated creatinine clearance < 60 ml/min) Chronic steroid therapy Known coronary artery disease Known causes of secondary hypertension Already taking Allopurinol Magnetic Resonance Imaging Exclusion Claustrophobia Cardiac implantable electronic device (permanent pacemaker and/or intracardiac defibrillator) Metal clips and/devices or other item that specifically prohibit safe CMR