Oral Nitrite for Older Heart Failure With Preserved Ejection Fraction

Study Overview
=================
Brief Summary
-----------------
This is a randomized double blinded controlled trial of 20-40 mg sodium nitrite tid in subjects with HFpEF. Primary outcomes are measures of physical function with non-invasive and invasive cardiopulmonary exercise testing, and fatigability, skeletal muscle bioenergetics, serology including inflammatory markers and platelet bioenergetics, quality of life measures.

Detailed Description
-----------------
Age-related physiological changes predispose to heart failure with preserved ejection fraction (HFpEF). Thus, HFpEF prevalence is escalating as the older population expands. High mortality and morbidity, diminished quality of life, and spiraling healthcare costs are typical consequences, and no effective HFpEF therapy is known. Therefore, several small exercise training (ExT) trials for HFpEF stand out by showing that ExT result in improved aerobic exercise capacity and infer that ExT constitutes novel substantive therapy. Nonetheless, such benefit was evident only after months of moderate to high intensity ExT; regimens that are unfeasible for most patients. In fact, poor compliance with ExT is typical in most HFpEF patients. The investigators propose there are intrinsic physiological components of HFpEF pathophysiology that predispose to fatigability. The investigators advance the concept of fatigability by quantifying it as a performance-based measure; i.e., subjective tiring during a standardized steady-state walking (perceived fatigability) and deterioration of self-selected walking speed over time (performance fatigability). The investigators assert that therapies to reduce fatigability will enhance HFpEF outcomes. Ongoing studies reveal pleiotropic benefits of oral inorganic nitrite (NO2), including enhanced performance of skeletal muscle (metabolism and bioenergetics) and vasomotor responses (systemic and pulmonary). The investigators' pilot work shows safety and biological efficacy of oral NO2 capsules. Thus, the investigators propose a randomized, controlled, double-blinded trial to study oral NO2 therapy in older (≥70 years) HFpEF patients. Aim 1 explores the utility of NO2 capsules to reduce perceived and performance fatigability (rated perceived exertion), improve aerobic capacity (peak oxygen uptake) and increase daily activity (accelerometry). Aim 2 delineates the mediating processes by which NO2 benefits are achieved. Skeletal muscle determinants are differentiated from the right and left heart vasomotor dynamics by integrating assessments using 31Phosphorus magnetic resonance spectroscopy and percutaneous needle muscle biopsies with those made using non-invasive and invasive cardiopulmonary exercise testing, near infrared spectroscopy and other techniques. The principal investigator is trained geriatrics and cardiology, and is solidly oriented to the dynamics of aging and cardiovascular disease (clinically and mechanistically) with particular expertise in functional assessment and skeletal muscle gene expression as determinants of performance. The investigative team provides formidable synergies that are well-suited to this translational investigation of systemic, cellular, and sub-cellular physiological dynamics. Our proposal is significant in multiple respects: 1) HFpEF is endemic with aging and constitutes a critical contemporary healthcare challenge today's growing population of older adults. 2) Fatigability is rooted in HFpEF pathophysiology, but it has not previously been addressed as a key part of management. 3) NO2 therapy is a novel and compelling therapeutic strategy. 4) Mechanisms underlying fatigability are clarified; we advance principles of patient-centered care by clarifying mechanisms that underlie a patient's experience of fatigability.

Official Title
-----------------
Nitrite Benefits to Mediate Fatigability in Older HFpEF Patients

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Drug: sodium nitrite
* Drug: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥70 years Diagnosis of HFpEF [adapted from the 2016 European Society of Cardiology (ESC) Guidelines to include: 1. Prior diagnosis of HF via one of these: medical record diagnosis by attending cardiologist verbal confirmation of HFpEF with attending cardiologist PI review of medical record to confirm HFpEF AND 2. Ejection Fraction % ≥40 Clinically stable (euvolemic; baseline heart rate <100 bpm) and without hospitalization or invasive cardiac procedure for 6 weeks Patients using 81 milligram (mg) aspirin (ASA) will be eligible, but will be asked to hold the medication for 3 days prior to biopsy. This technique has previously been used with consistent safety. Patients will also be asked to avoid non-steroidal anti-inflammatory medications (NSAIDs) for 2 days prior to the biopsy. Patients using anti-thrombin and anti-platelet therapy will plan to modify prior to muscle biopsies individually in coordination with the participant's primary cardiologist. Exclusion Criteria: Allergy to lidocaine BP >180/95 or <100/60 Anemia: Hgb<11.0 (♂),10.0 (♀) Dementia or inability to give informed consent End-stage malignancy Severe orthopedic exercise limitation Use of chronic oral corticosteroids or other medications that affect muscle function. Chronic alcohol or drug dependency. Any bleeding disorder that would contraindicate biopsy such as history of clinically significant bleeding diathesis (e.g., Hemophilia A or B, Von Willebrand's Disease or congenital Factor VII deficiency). Psychiatric hospitalization within the last 3 months Major cardiovascular event or procedure within the prior 6 weeks HF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction). If valve replacement has been performed, patient may not be enrolled for 12 months after this procedure. Severe uncorrected primary valvular heart disease (if valve replacement has been performed, patients will not be eligible for at least 12 months) Mechanical valve replacement requiring warfarin Peripheral or pulmonary artery disease Currently taking clopidogrel for a recent stent placement and/or a complex atherosclerotic lesion such that holding clopidogrel creates disproportionate risk. Current use of organic nitrates or phosphodiesterase type 5 inhibitors (PDE5s) Unable to hold warfarin or use bridging therapy, or to hold aspirin for 3 days (81 mg), 3 days (325 mg) prior to muscle biopsy or thienopyridine medications for 5 days prior to muscle biopsy. Subjects with diabetes whose HgbA1c >10.0 Other chronic unstable disease such as active neoplasm, end stage chronic kidney, liver or other organ disease,

Ages Eligible for Study
-----------------
Minimum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>20 or 40 mg sodium nitrite tid | Drug: sodium nitrite<br>* Subjects to receive active study drug three times daily during treatment period and then post treatment testing period.<br>* Other names: nitrite;|
| Placebo Comparator: Control<br>20 or 40 mg placebo tid | Drug: Control<br>* Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period.<br>* Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiorespiratory Fitness | Assessment of peak Oxygen uptake (VO2) maximum via symptom limited exercise testing | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perceived Fatigability | Assessment of Rate of Perceived Exertion (RPE) during steady state exercise testing at the last minute of the test. The RPE scale (Rate of Perceived Exertion) goes from 6-20 with a higher number indicating more effort and possibly a worse outcome. | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | 
| Bioenergetics: In-Vivo 31P MRS Respirations | Phosphocreatine reuptake after exercise during the kicking exercise in the 31P MRS (magnetic resonance spectroscopy) | Week 3 (pre drug) to week 10(post drug); approx. 8 weeks | 
| Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | Mitochondrial respiration was analyzed by assessing O2 consumption by skeletal muscle mitochondria at Energetic State 3.1 using the Oroboros instrument. This state is generally used a marker for mitochondrial efficiency. Increases in consumption are generally linked to a better outcome. | Week 5 (pre-drug) to week 16 (post-drug); approx. 8 weeks | 
| Exercise-induced Changes in Pulmonary Arterial Pressure | Pulmonary arterial pressure, an indication of cardiopulmonary hemodynamics and cardiac function, was measured at rest and at peak exercise during an invasive cardiopulmonary exercise test. | Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks | 
| Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | Pulmonary capillary wedge pressure, an indication of cardiopulmonary hemodynamics and cardiac function, was measured at rest and at peak exercise during an invasive cardiopulmonary exercise test. | Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks | 
| Patients With Pulmonary Hypertension | Right Ventricular-Pulmonary Artery Coupling, assessed by right ventricular ejection fraction (RVEF) and pulmonary artery systolic pressure (PASP), decreases with worsening right heart failure. We will be measuring this by assessing RVEF and PASP during invasive cardiopulmonary exercise testing in patients that meet criteria for pulmonary hypertension. | Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks | 
| Steps From Accelerometry Assessment of Daily Activity | Actigraph device-specific activity steps on daily-wear wrist device based on movement. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 
| Sedentary Events From Accelerometry Assessment of Daily Activity | Assessment of daily activity using accelerometry on a daily-wear wrist device. Sedentary bout is a triggered stint of time that the patient is not moving or has low level of activity sensed by the accelerometer. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 
| Light Activity Duration From Accelerometry Assessment of Daily Activity | Assessment of daily activity using accelerometry on a daily-wear wrist device. Light activity is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 
| Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | Assessment of daily activity using accelerometry on a daily-wear wrist device. MVPA is Moderate-to-vigorous physical activity that is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 
| Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Assessment of daily activity using accelerometry on a daily-wear wrist device. Vector Magnitude in counts per day are accelerations in 3 dimensions that indicate activity. More counts is associated with more activity. More counts in a shorter duration of time indicate light, moderate, and vigorous activity. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 
| Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Assessment of daily activity using accelerometry on a daily-wear wrist device. Sedentary bout is a triggered stint of time that the patient is not moving or has low level of activity sensed by the accelerometer. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 
| Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | Assessment of daily activity using accelerometry on a daily-wear wrist device. Light activity is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 
| Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | Assessment of daily activity using accelerometry on a daily-wear wrist device. MVPA is Moderate-to-vigorous physical activity that is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate. | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks |