Exercise and NO in HFrEF

Heart failure with reduced ejection fraction (HFrEF), a clinical syndrome that develops as a
consequence of heart disease from multiple etiologies, now affects almost six million
Americans, presenting an imminent need for further research addressing the pathophysiology of
this pervasive disease. One of the most damaging consequences of the disease is an elevation
in sympathetic nervous system (SNS) activity, which manifests peripherally as chronic
vasoconstriction. In HFrEF patients, peripheral vasoconstriction acts to limit blood flow in
the exercising muscle, promoting exercise intolerance, premature skeletal muscle fatigue,
inactivity, and a subsequent acceleration in disease progression. Fortunately,
disease-related sympathoexcitation may be remediable. Among the most influential modulators
of peripheral SNS expression is the nitric oxide (NO) pathway. Thus, interventions focused on
improving NO bioavailability may offer a new, unexplored strategy for inhibiting SNS
overactivity in HFrEF, and thus represent a novel approach for improving and exercise
tolerance.

Specific Aim 1 will utilize an oral antioxidant (AOx) cocktail to study whether disruptions
in oxidative stress can favorably influence exercise tolerance in HFrEF patients.

Specific Aim 2 will examine the efficacy of oral tetrahydrobiopterin (BH4), a cofactor for
endothelial nitric oxide synthase (eNOS), to improve exercise intolerance in HFrEF patients.

Specific Aim 3 will examine the therapeutic potential of aerobic, knee-extensor (KE) exercise
training to improve skeletal muscle blood flow and thus exercise tolerance in HF patients.
Importantly, this exercise modality produces a potent training stimulus without the
significant cardiopulmonary stress that accompanies more traditional, whole-body exercise. It
is proposed that 12 weeks of supervised KE training will increase NO bioavailability and
inhibit SNS activity, which will in turn improve vascular function and exercising limb blood
flow.

Specific Aim 4 will examine whether the interventional strategies in Aims 1-3 can improve
adherence to an 8-week clinical cardiac rehabilitation program. It is hypothesized that
chronic AOx consumption (Aim 1), BH4 consumption (Aim 2), and aerobic exercise training (Aim
3) interventions will reduce the rate of attrition from Phase II outpatient Cardiac
Rehabilitation in HFrEF patients compared to patients that did not participate in an
interventional phase of the study.

The investigators anticipate that disrupting this "vicious cycle" of vasoconstriction in
HFrEF may improve overall vascular health to such a degree that significant improvements in
exercise-related symptoms are realized, which could therefore improve enrollment in a cardiac
rehabilitation program. In this context, findings from the proposed work may provide an
important link between vascular and rehabilitative medicine, thus serving to refine current
strategies for the treatment of Veterans with HFrEF, ultimately leading to enhanced quality
of life in this cohort.

Inclusion Criteria:

General Inclusion/Exclusion Criteria:

- The study group will include subjects with a history of stable cardiomyopathy
(ischemic and non-ischemic, >3 months duration, ages 45-75 yrs) despite a minimum of 6
weeks of optimal treatment.

- Optimal therapy will be according to American Heart Association (AHA) /American
College of Cardiology (ACC) and Heart Failure Society of America (HFSA) HF guidelines,
including treatment with angiotensin-converting enzyme (ACE) and -blocker therapy (for
at least 6 weeks), or have documented reason for variation, including medication
intolerance, contraindication, patient preference, or personal physician's judgment.

- Patient enrollment will be limited to those individuals with New York Heart
Association (NYHA) class II and III symptoms, left ventricular ejection fraction <35%
(LVEF), with no or minimal smoking history (<15 pk yrs), and without pacemakers.

Exclusion Criteria:

- Patients with atrial fibrillation or HF believed to be secondary to atrial
fibrillation will be excluded.

- Patients with HF secondary to significant uncorrected primary valvular disease (except
mitral regurgitation secondary to left ventricular dysfunction) will also be excluded.

- Patients will be sedentary, defined here as no regular physical activity for at least
the prior 6 months and current activity level will be documented by an activity
questionnaire.

- Patients must have no orthopedic limitations that would prohibit them from performing
knee-extensor exercise.

- Due to the typical age of patients with HF, all women will be postmenopausal (either
natural or surgical) defined as a cessation of menses for at least 2 years, and in
women without a uterus, follicle stimulating hormone (FSH) >40 IU/L.

- Women currently taking hormone replacement therapy (HRT) will be excluded from the
proposed studies due to the direct vascular effects of HRT Comorbidity Exclusion
Criteria: Patients with significant non-cardiac comorbidities, which if present could
alter the study results, will be excluded.

- These include a diagnosis of Dementia

- Severe chronic obstructive pulmonary disease (COPD)

- Peripheral Vascular Disease

- Anemia

- Sleep-related Breathing Disorder

- Severe Valvular Heart Disease

- Diabetes (if on insulin therapy)

- or End-stage Malignancy

- The investigators will also exclude morbidly obese patients (BMI >40), patients with
uncontrolled Hypertension (>160/100), Anemia (Hgb<9) and Severe Renal Insufficiency
(individuals with creatinine clearance <30 by the Cockcroft-Gault formula).