Rhode Island Diastolic Dysfunction - Heart Failure

Congestive heart failure carries a significant epidemiologic and economic burden in today's
healthcare system and is associated with increased morbidity and mortality in those affected.

There are approximately 5 million people in the United States with heart failure, and of
those, nearly half have heart failure with preserved ejection fraction (HFpEF). HFpEF, also
referred to as diastolic heart failure, is a clinical syndrome characterized by prolonged
relaxation of the myocardium resulting in symptoms including dyspnea, edema, fatigue, and
decreased exercise tolerance, which are clinically indistinguishable from the presentation of
heart failure with reduced ejection fraction (HFrEF). The underlying mechanisms in diastolic
dysfunction are not clearly elucidated, making targeted therapy a challenge. There are
currently no FDA approved treatments for this syndrome, and multiple clinical trials have
demonstrated that standard treatments for systolic heart failure are ineffective in treating
diastolic dysfunction. One of the proposed underlying mechanisms of diastolic dysfunction is
via the reduction of nitric oxide (NO), an endothelium-derived vasodilator that regulates
blood pressure and regional blood flow. In 2010, Silberman et al. examined the effect of
cardiac oxidation on nitric oxide and found that depletion of tetrahydrobiopterin (BH4), an
essential cofactor in the production of nitric oxide, causes uncoupling of nitric oxide
synthase, impaired relaxation of cardiac myocytes, and leads to subsequent diastolic
dysfunction. The authors further went on to demonstrate that treatment with BH4 can improve
diastolic dysfunction in a hypertensive mouse model as well as in isolated cardiac myocytes
and may play a role in the treatment of HFpEF.

To the investigators' knowledge, the role of BH4 in treating diastolic dysfunction in human
subjects has not been studied.

Inclusion Criteria:

1. Male and female U.S. Veteran patients over the age of eighteen, with echocardiographic
findings of >= Grade 2 diastolic dysfunction [as per American Society of
Echocardiography guidelines] and

2. Diagnosis of hypertension, diabetes, or heart failure in medical records.

3. Eligible subjects must be ambulatory (not dependent on any ambulatory assist devices
including cane or walker).

Exclusion Criteria:

1. Any history of documented ejection fraction <50%

2. Significant COPD (defined as oxygen-dependent COPD)

3. Acute coronary syndrome within the past three months defined by EKG changes and
biomarkers of myocardial necrosis (ie. elevated troponin) in the setting of chest pain
or an anginal equivalent)

4. Presence of hypertrophic cardiomyopathy

5. Presence of infiltrative/restrictive cardiomyopathy

6. Echocardiographic evidence of moderate or severe aortic or mitral valve stenosis or
regurgitation

7. Previously diagnosed phenylketonuria

8. End stage renal disease requiring hemodialysis

9. Pre-existing seizure disorder

10. Terminal illness (not including heart failure) with expected survival of one year or
less

11. Females who are pregnant or breastfeeding. All females of child bearing age will
undergo pregnancy testing prior to randomization.

12. Recent hospitalization within three months.

13. Previous Bioprosthetic and/or mechanical aortic or mitral valves