Heart Failure
Conditions
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.
Interventions
DRUGsodium nitrite
Subjects to receive active study drug three times daily during treatment period and then post treatment testing period.
DRUGControl
Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period.
Sponsors
National Institute on Aging (NIA)
Gladwin, Mark, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
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,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiorespiratory Fitness | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Assessment of peak Oxygen uptake (VO2) maximum via symptom limited exercise testing |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bioenergetics: In-Vivo 31P MRS Respirations | Week 3 (pre drug) to week 10(post drug); approx. 8 weeks | Phosphocreatine reuptake after exercise during the kicking exercise in the 31P MRS (magnetic resonance spectroscopy) |
| Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | Week 5 (pre-drug) to week 16 (post-drug); approx. 8 weeks | 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. |
| Exercise-induced Changes in Pulmonary Arterial Pressure | Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks | 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. |
| Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks | 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. |
| Patients With Pulmonary Hypertension | Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks | 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. |
| Steps From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | Actigraph device-specific activity steps on daily-wear wrist device based on movement. |
| Perceived Fatigability | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | 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. |
| Light Activity Duration From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 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. |
| Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 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. |
| Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 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. |
| Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 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. |
| Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 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. |
| Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 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. |
| Sedentary Events From Accelerometry Assessment of Daily Activity | Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin | Week 1 pre drug to week 16 post drug | Change in hemoglobin |
| Hemodynamics; Blood Pressure | Week 1 pre drug to week 16 post drug | Change in Blood pressure |
| Hemodynamics; Heart Rate | Week 1 pre drug to week 16 post drug | Change in heart rate |
| Muscle Protein | Week 5 (pre drug) to week 16 (post drug); approx. 8 week | Change in protein content of muscle fiber |
| Near Infrared Spectroscopy | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Assessment of blood flow during exercise |
| Pain | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in pre and post scores on the McGill Pain Questionnaire |
| Physical Frailty and Balance | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in score on Standard Physical Performance Battery at visit 2 pre drug and visit 5 |
| Physical Activity | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in pre and post scores on the CHAMPS (Community Healthy Activities Program for Seniors) Activities Questionnaire for Older Adults-physical activity |
| Quality of Life | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in pre and post scores on the Kansas City Cardiomyopathy Questionnaire subject self reported responses |
| Submaximal Exercise Performance | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in distance on six minute walk test |
| Self-efficacy | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in pre and post scores on the Sullivan Cardiac Self Efficacy questionnaire |
| Adiponectin | Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks | Change in adiponectin |
| Thyroid Stimulating Hormone | Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks | Change in thyroid stimulating hormone (TSH) |
| Blood Nitrate | Week 5 (pre drug) to week 16 (post drug); approx. 8 week | Change in blood levels to assess efficacy of study drug |
| Brain Natriuretic Protein | Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks | Change in brain natriuretic protein (BNP) |
| Cardiopulmonary Exercise Testing: iCPET | Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks | Invasive cardiopulmonary exercise testing |
| Cardiopulmonary Exercise Testing; nCPET | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Non-invasive cardiopulmonary exercise testing |
| Cognitive Function | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in pre and post scores on the Montreal Cognitive Assessment |
| Co-morbid Illness | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in pre and post scores on the Charlson Comorbidity Index |
| Co-morbidity Medications | Week 1 pre drug to week 16 post drug | Medications for comorbidity managment |
| Echocardiogram | Week 1 pre-drug to week 16 post drug | Change in cardiac strain |
| Fatigability | Week 2(pre drug) to Week 10( post drug); approx. 8 weeks | Change in pre and post scores on the Pittsburgh Fatigability Index |
| Frailty Index Assessment | Week 1 screening pre-drug to week 16 post drug | Physician assessment of frailty using the Canadian Clinical Frailty Scale |
| Gene Expression | Week 5 (pre drug) to week 16 (post drug); approx. 8 week | Change in DNA from Polymerase Chain Reaction analysis |
| Glomerular Filtration Rate | Week 5 (pre drug) to week 16 (post drug); approx. 8 week | Change in glomerular filtration rate (GFR) |
| Glycosylated Hemoglobin | Week 5 (pre drug) to week 16 (post drug); approx. 8 week | Change in glycosylated hemoglobin (HgbA1c) |
| Hematocrit | Week 1 pre drug to week 16 post drug | Change in hematocrit |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sodium Nitrite 20 or 40 mg sodium nitrite tid
sodium nitrite: Subjects to receive active study drug three times daily during treatment period and then post treatment testing period. | 7 |
| Placebo 20 or 40 mg placebo tid
Control: Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period. | 8 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Failed Pharmacokinetics | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Sodium Nitrite | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 77.1 years STANDARD_DEVIATION 6.2 | 74.6 years STANDARD_DEVIATION 3.5 | 75.7 years STANDARD_DEVIATION 4.9 |
| Ejection Fraction | 50.9 Percentage of blood STANDARD_DEVIATION 10.1 | 54.8 Percentage of blood STANDARD_DEVIATION 9.7 | 51.4 Percentage of blood STANDARD_DEVIATION 9.7 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 7 participants | 8 participants | 15 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 8 |
| other Total, other adverse events | 3 / 7 | 7 / 8 |
| serious Total, serious adverse events | 0 / 7 | 0 / 8 |
Outcome results
Primary
Cardiorespiratory Fitness
Assessment of peak Oxygen uptake (VO2) maximum via symptom limited exercise testing
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Population: In the treatment arm, a subject withdrew after pre-treatment testing.~1 subject from the control arm withdrew after randomization but before testing. A second withdrew prior after pre-treatment testing, but before post-treatment testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Cardiorespiratory Fitness | VO2 at Rest, last 30 sec, Pre-treatment | 4.1 ml/kg/min | Standard Deviation 1.5 |
| Sodium Nitrite | Cardiorespiratory Fitness | VO2 at Peak Exercise, last 30 sec, Post-treatment | 19.6 ml/kg/min | Standard Deviation 7.9 |
| Sodium Nitrite | Cardiorespiratory Fitness | VO2 at Rest, last 30 sec, Post-treatment | 5.1 ml/kg/min | Standard Deviation 1 |
| Sodium Nitrite | Cardiorespiratory Fitness | VO2 at Peak Exercise, last 30 sec, change | 1.4 ml/kg/min | Standard Deviation 5.2 |
| Sodium Nitrite | Cardiorespiratory Fitness | VO2 at Peak Exercise, last 30 sec, Pre-treatment | 18.6 ml/kg/min | Standard Deviation 4.3 |
| Placebo | Cardiorespiratory Fitness | VO2 at Peak Exercise, last 30 sec, change | -3.4 ml/kg/min | Standard Deviation 5.2 |
| Placebo | Cardiorespiratory Fitness | VO2 at Rest, last 30 sec, Pre-treatment | 4.0 ml/kg/min | Standard Deviation 0.5 |
| Placebo | Cardiorespiratory Fitness | VO2 at Peak Exercise, last 30 sec, Pre-treatment | 19.0 ml/kg/min | Standard Deviation 3.9 |
| Placebo | Cardiorespiratory Fitness | VO2 at Peak Exercise, last 30 sec, Post-treatment | 15.9 ml/kg/min | Standard Deviation 7.7 |
| Placebo | Cardiorespiratory Fitness | VO2 at Rest, last 30 sec, Post-treatment | 4.5 ml/kg/min | Standard Deviation 0.8 |
Secondary
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.
Time frame: Week 5 (pre-drug) to week 16 (post-drug); approx. 8 weeks
Population: Smaller amount of subjects were analyzed due to unexpected problems with specialized testing equipment availability.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | O2 Consumption, Pre-treatment | 34.6 pmol/(s*mg) | Standard Deviation 16.5 |
| Sodium Nitrite | Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | O2 Consumption, Post-treatment | 61.6 pmol/(s*mg) | Standard Deviation 36.2 |
| Sodium Nitrite | Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | O2 Consumption, Overall change | 27.1 pmol/(s*mg) | Standard Deviation 27.4 |
| Placebo | Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | O2 Consumption, Pre-treatment | 57.7 pmol/(s*mg) | Standard Deviation 14.8 |
| Placebo | Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | O2 Consumption, Post-treatment | 46.0 pmol/(s*mg) | Standard Deviation 20 |
| Placebo | Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis | O2 Consumption, Overall change | -11.7 pmol/(s*mg) | Standard Deviation 11.3 |
Secondary
Bioenergetics: In-Vivo 31P MRS Respirations
Phosphocreatine reuptake after exercise during the kicking exercise in the 31P MRS (magnetic resonance spectroscopy)
Time frame: Week 3 (pre drug) to week 10(post drug); approx. 8 weeks
Population: Magnetic resonance spectroscopy equipment had unexpected limited availability, which is why so few participants were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Bioenergetics: In-Vivo 31P MRS Respirations | K PCr, Pre-treatment | .028 1/s | Standard Deviation 0.003 |
| Sodium Nitrite | Bioenergetics: In-Vivo 31P MRS Respirations | K PCr, Post-treatment | .028 1/s | Standard Deviation 0.011 |
| Placebo | Bioenergetics: In-Vivo 31P MRS Respirations | K PCr, Pre-treatment | .019 1/s | Standard Deviation 0 |
| Placebo | Bioenergetics: In-Vivo 31P MRS Respirations | K PCr, Post-treatment | .022 1/s | Standard Deviation 0 |
Secondary
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.
Time frame: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
Population: Smaller amount of subjects were analyzed due to unexpected problems with specialized testing equipment availability.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Rest, Pre-treatment | 11.0 mmHg | Standard Deviation 4.2 |
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Rest, Post-treatment | 17.5 mmHg | Standard Deviation 7.8 |
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Peak Exercise, Pre-treatment | 28.5 mmHg | Standard Deviation 5 |
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Peak Exercise, Post-treatment | 29.0 mmHg | Standard Deviation 1.4 |
| Placebo | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Peak Exercise, Post-treatment | 34.7 mmHg | Standard Deviation 13.7 |
| Placebo | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Rest, Pre-treatment | 16.0 mmHg | Standard Deviation 2 |
| Placebo | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Peak Exercise, Pre-treatment | 41.7 mmHg | Standard Deviation 15.1 |
| Placebo | Exercise-induced Changes in Pulmonary Arterial Pressure | mPAP at Rest, Post-treatment | 15.3 mmHg | Standard Deviation 1.5 |
Secondary
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.
Time frame: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
Population: Smaller amount of subjects were analyzed due to unexpected problems with specialized testing equipment availability.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Rest, Pre-treatment | 5.5 mmHg | Standard Deviation 0.7 |
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Rest, Post-treatment | 8.5 mmHg | Standard Deviation 12 |
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Peak Exercise, Pre-treatment | 11.0 mmHg | Standard Deviation 0 |
| Sodium Nitrite | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Peak Exercise, Post-treatment | 11.5 mmHg | Standard Deviation 7.8 |
| Placebo | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Peak Exercise, Post-treatment | 20.3 mmHg | Standard Deviation 10.6 |
| Placebo | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Rest, Pre-treatment | 8.3 mmHg | Standard Deviation 2.1 |
| Placebo | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Peak Exercise, Pre-treatment | 22.7 mmHg | Standard Deviation 5.5 |
| Placebo | Exercise-induced Changes in Pulmonary Capillary Wedge Pressure | PCWP at Rest, Post-treatment | 5.7 mmHg | Standard Deviation 5 |
Secondary
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.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Light Activity Duration From Accelerometry Assessment of Daily Activity | Light activity (sec/day), Pre-treatment | 3288 seconds/day | Standard Deviation 715 |
| Sodium Nitrite | Light Activity Duration From Accelerometry Assessment of Daily Activity | Light activity (sec/day), Post-treatment | 2866 seconds/day | Standard Deviation 501 |
| Sodium Nitrite | Light Activity Duration From Accelerometry Assessment of Daily Activity | Light activity (sec/day), Change | -422 seconds/day | Standard Deviation 903 |
| Placebo | Light Activity Duration From Accelerometry Assessment of Daily Activity | Light activity (sec/day), Pre-treatment | 3317 seconds/day | Standard Deviation 340 |
| Placebo | Light Activity Duration From Accelerometry Assessment of Daily Activity | Light activity (sec/day), Post-treatment | 3224 seconds/day | Standard Deviation 793 |
| Placebo | Light Activity Duration From Accelerometry Assessment of Daily Activity | Light activity (sec/day), Change | -94 seconds/day | Standard Deviation 814 |
Secondary
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.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | % in Light Activity, Pre-Treatment | .320 % of day | Standard Deviation 0.041 |
| Sodium Nitrite | Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | % in Light Activity, Post-Treatment | .306 % of day | Standard Deviation 0.033 |
| Sodium Nitrite | Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | % in Light Activity,Change | -0.014 % of day | Standard Deviation 0.046 |
| Placebo | Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | % in Light Activity, Pre-Treatment | .359 % of day | Standard Deviation 0.026 |
| Placebo | Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | % in Light Activity, Post-Treatment | .359 % of day | Standard Deviation 0.327 |
| Placebo | Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity | % in Light Activity,Change | -0.033 % of day | Standard Deviation 0.078 |
Secondary
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.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | MVPA, Pre-treatment | 719.3 minutes/day | Standard Deviation 597.1 |
| Sodium Nitrite | Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | MVPA, Post-treatment | 507.8 minutes/day | Standard Deviation 456.3 |
| Sodium Nitrite | Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | MVPA, Change | -211.5 minutes/day | Standard Deviation 589.9 |
| Placebo | Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | MVPA, Pre-treatment | 545.8 minutes/day | Standard Deviation 237.3 |
| Placebo | Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | MVPA, Post-treatment | 548.2 minutes/day | Standard Deviation 255.3 |
| Placebo | Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity | MVPA, Change | 2.333 minutes/day | Standard Deviation 254.4 |
Secondary
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.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | % in MVPA, Pre-treatment | 0.066 Percentage of day | Standard Deviation 0.041 |
| Sodium Nitrite | Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | % in MVPA, Post-treatment | 0.054 Percentage of day | Standard Deviation 0.045 |
| Sodium Nitrite | Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | % in MVPA, Change | -0.012 Percentage of day | Standard Deviation 0.032 |
| Placebo | Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | % in MVPA, Pre-treatment | 0.059 Percentage of day | Standard Deviation 0.023 |
| Placebo | Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | % in MVPA, Post-treatment | 0.055 Percentage of day | Standard Deviation 0.025 |
| Placebo | Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity | % in MVPA, Change | -0.004 Percentage of day | Standard Deviation 0.023 |
Secondary
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.
Time frame: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
Population: Smaller amount of subjects were analyzed due to unexpected problems with specialized testing equipment availability.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Nitrite | Patients With Pulmonary Hypertension | 0 Participants |
| Placebo | Patients With Pulmonary Hypertension | 0 Participants |
Secondary
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.
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Population: In the treatment arm, a subject withdrew after pre-treatment testing.~1 subject from the control arm withdrew after randomization but before testing. A second withdrew prior after pre-treatment testing, but before post-treatment testing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Perceived Fatigability | RPE during last minute of the test, Pre-treatment | 9.1 Units on a scale | Standard Deviation 2.6 |
| Sodium Nitrite | Perceived Fatigability | RPE during last minute of the test, Post-treatment | 8.3 Units on a scale | Standard Deviation 1.5 |
| Sodium Nitrite | Perceived Fatigability | RPE during last minute of the test, Change | -1.2 Units on a scale | Standard Deviation 2 |
| Placebo | Perceived Fatigability | RPE during last minute of the test, Pre-treatment | 10.8 Units on a scale | Standard Deviation 4 |
| Placebo | Perceived Fatigability | RPE during last minute of the test, Post-treatment | 10.3 Units on a scale | Standard Deviation 3.3 |
| Placebo | Perceived Fatigability | RPE during last minute of the test, Change | -0.2 Units on a scale | Standard Deviation 1.6 |
Secondary
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.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Average Sedentary Bout Duration, Pre | 14.8 minutes/bout | Standard Deviation 3 |
| Sodium Nitrite | Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Average Sedentary Bout Duration, Post | 14.4 minutes/bout | Standard Deviation 2.2 |
| Sodium Nitrite | Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Average Sedentary Bout Duration, Chg | -0.4 minutes/bout | Standard Deviation 2.4 |
| Placebo | Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Average Sedentary Bout Duration, Pre | 13.6 minutes/bout | Standard Deviation 2.3 |
| Placebo | Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Average Sedentary Bout Duration, Post | 12.0 minutes/bout | Standard Deviation 6 |
| Placebo | Sedentary Event Duration From Accelerometry Assessment of Daily Activity | Average Sedentary Bout Duration, Chg | -1.6 minutes/bout | Standard Deviation 4.9 |
Secondary
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.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Sedentary Events From Accelerometry Assessment of Daily Activity | # of sedentary bouts/day, Pre-treatment | 29.7 bouts/day | Standard Deviation 28.5 |
| Sodium Nitrite | Sedentary Events From Accelerometry Assessment of Daily Activity | # of sedentary bouts/day, Post-treatment | 23.7 bouts/day | Standard Deviation 27.6 |
| Sodium Nitrite | Sedentary Events From Accelerometry Assessment of Daily Activity | # of sedentary bouts/day, Change | -6.0 bouts/day | Standard Deviation 31.3 |
| Placebo | Sedentary Events From Accelerometry Assessment of Daily Activity | # of sedentary bouts/day, Pre-treatment | 24.0 bouts/day | Standard Deviation 17.2 |
| Placebo | Sedentary Events From Accelerometry Assessment of Daily Activity | # of sedentary bouts/day, Post-treatment | 24.7 bouts/day | Standard Deviation 24.3 |
| Placebo | Sedentary Events From Accelerometry Assessment of Daily Activity | # of sedentary bouts/day, Change | 0.7 bouts/day | Standard Deviation 17.4 |
Secondary
Steps From Accelerometry Assessment of Daily Activity
Actigraph device-specific activity steps on daily-wear wrist device based on movement.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Steps From Accelerometry Assessment of Daily Activity | Actigraph Steps, Pre-treatment | 58399 Counts/day | Standard Deviation 22586 |
| Sodium Nitrite | Steps From Accelerometry Assessment of Daily Activity | Steps, Post-treatment | 48741 Counts/day | Standard Deviation 25534 |
| Sodium Nitrite | Steps From Accelerometry Assessment of Daily Activity | Steps, Change | -9657 Counts/day | Standard Deviation 30110 |
| Placebo | Steps From Accelerometry Assessment of Daily Activity | Actigraph Steps, Pre-treatment | 54122 Counts/day | Standard Deviation 14213 |
| Placebo | Steps From Accelerometry Assessment of Daily Activity | Steps, Post-treatment | 53757 Counts/day | Standard Deviation 18107 |
| Placebo | Steps From Accelerometry Assessment of Daily Activity | Steps, Change | -366 Counts/day | Standard Deviation 18251 |
Secondary
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.
Time frame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Population: Only 6 subjects in either arm had functioning accelerometers with data that could be extracted and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Nitrite | Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Vector Magnitude, Pre-treatment | 1192.5 Counts/day | Standard Deviation 379.5 |
| Sodium Nitrite | Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Vector Magnitude, Post-treatment | 1043 Counts/day | Standard Deviation 357 |
| Sodium Nitrite | Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Vector Magnitude, Change | -149.4 Counts/day | Standard Deviation 329 |
| Placebo | Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Vector Magnitude, Pre-treatment | 1205 Counts/day | Standard Deviation 205 |
| Placebo | Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Vector Magnitude, Post-treatment | 1122.7 Counts/day | Standard Deviation 318.5 |
| Placebo | Vector Magnitude Counts From Accelerometry Assessment of Daily Activity | Vector Magnitude, Change | -82.3 Counts/day | Standard Deviation 337.3 |
Other Pre-specified
Adiponectin
Change in adiponectin
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Other Pre-specified
Blood Nitrate
Change in blood levels to assess efficacy of study drug
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other Pre-specified
Brain Natriuretic Protein
Change in brain natriuretic protein (BNP)
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Other Pre-specified
Cardiopulmonary Exercise Testing: iCPET
Invasive cardiopulmonary exercise testing
Time frame: Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
Other Pre-specified
Cardiopulmonary Exercise Testing; nCPET
Non-invasive cardiopulmonary exercise testing
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Cognitive Function
Change in pre and post scores on the Montreal Cognitive Assessment
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Co-morbid Illness
Change in pre and post scores on the Charlson Comorbidity Index
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Co-morbidity Medications
Medications for comorbidity managment
Time frame: Week 1 pre drug to week 16 post drug
Other Pre-specified
Echocardiogram
Change in cardiac strain
Time frame: Week 1 pre-drug to week 16 post drug
Other Pre-specified
Fatigability
Change in pre and post scores on the Pittsburgh Fatigability Index
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Frailty Index Assessment
Physician assessment of frailty using the Canadian Clinical Frailty Scale
Time frame: Week 1 screening pre-drug to week 16 post drug
Other Pre-specified
Gene Expression
Change in DNA from Polymerase Chain Reaction analysis
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other Pre-specified
Glomerular Filtration Rate
Change in glomerular filtration rate (GFR)
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other Pre-specified
Glycosylated Hemoglobin
Change in glycosylated hemoglobin (HgbA1c)
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other Pre-specified
Hematocrit
Change in hematocrit
Time frame: Week 1 pre drug to week 16 post drug
Other Pre-specified
Hemodynamics; Blood Pressure
Change in Blood pressure
Time frame: Week 1 pre drug to week 16 post drug
Other Pre-specified
Hemodynamics; Heart Rate
Change in heart rate
Time frame: Week 1 pre drug to week 16 post drug
Other Pre-specified
Hemoglobin
Change in hemoglobin
Time frame: Week 1 pre drug to week 16 post drug
Other Pre-specified
Muscle Protein
Change in protein content of muscle fiber
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other Pre-specified
Near Infrared Spectroscopy
Assessment of blood flow during exercise
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Pain
Change in pre and post scores on the McGill Pain Questionnaire
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Physical Activity
Change in pre and post scores on the CHAMPS (Community Healthy Activities Program for Seniors) Activities Questionnaire for Older Adults-physical activity
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Physical Frailty and Balance
Change in score on Standard Physical Performance Battery at visit 2 pre drug and visit 5
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Quality of Life
Change in pre and post scores on the Kansas City Cardiomyopathy Questionnaire subject self reported responses
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Self-efficacy
Change in pre and post scores on the Sullivan Cardiac Self Efficacy questionnaire
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Submaximal Exercise Performance
Change in distance on six minute walk test
Time frame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other Pre-specified
Thyroid Stimulating Hormone
Change in thyroid stimulating hormone (TSH)
Time frame: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks