Dietary Nitrate for Heart Failure

For all studies and sub-studies:

A) All Subjects will be consented. B) All Subjects will give permission for the investigators to review their medical records.

For the BRJ main study (acute dose BRJ intervention):

• After consenting to participate, subjects will be instructed to refrain from spitting or the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum during the study.
• Subjects will be asked to answer questionnaires regarding their medical health (basic health questionnaire, Minnesota living with heart failure questionnaire, a magnetic resonance safety -i.e., questions regarding implanted pacemakers, etc...) 2a)Subjects will undergo a physical examination at one time during the study.
• Subjects will be interviewed by a dietician with regards to their typical dietary intake and instructed on a low nitrate diet.
• In study visit #1 subjects will be randomized to receive either a "shot" of BRJ (James White Drinks)or placebo (BRJ without nitrates).
• Before and at 3 time points (~hourly) after receiving the BRJ or placebo, subjects will undergo phlebotomy for plasma nutrient/hormone levels and will have their blood pressure checked. They will also be asked to swish (5 minutes) and spit out a dilute ~ 4tbps solution of nitrate,so we can quantify nitrate to nitrite conversion at ~ 1 1/4 hours after ingestion 5A) Subjects will undergo an echocardiogram just after the swish and spit.
• ~ 1 3/4 hours after ingestion, subjects will undergo a 6 minute walk.
• ~ 2 hours after ingestion, subjects will pedal an ergometer for 6 min at 15, 30, and 45 W (requiring ~50, ~60, and ~70% of oxygen consumption (VO2) peak, i.e., peak oxygen consumption) while VO2 is measured using a ParvoMedics TrueOne (this is the brand) metabolic cart. Five min of rest will be allowed between stages. The average VO2 during the last 2 min of each stage will be used to calculate gross and delta efficiency using stoichiometric equations as previously described. Following a 10 min rest period, peak power and VO2 peak will determined during a continuous exercise test performed using a 10 W/min ramp protocol.
• Subjects will then (immediately afterwards )undergo an Magnetic resonance (MR) study of skeletal muscle (and if there is time cardiac performance) with mild exercise (pushing one foot on a pedal for 6 min of submaximal isometric exercise (1 s contraction at 50% of previously-determined maximal voluntary contraction - according to their VO2 peak levels in their medical charts - every 9 s) with spectra acquired before, during, and after exercise.

During exercise, subjects will have their heart rate, blood pressure and rhythm monitored.

• Subjects will be asked to undergo a mouth swab for bacterial DNA analyses (after the swish and spit) 9A) Subjects will undergo a Dual-energy Xray absorptiometry (DXA) scan for body composition analysis (either before or after BRJ ingestion - it is a phenotyping measure - not an endpoint)
• Subjects will undergo a 7 d wash-out period
• Subjects will come in for study day 2 in which they will receive whichever treatment (BRJ or placebo) that they did not receive at first and then repeat the studies listed above 5)-9).

(The total time of the study is estimated to take 5 hours)

For the longer 2 (or 4) week BRJ substudy: (subjects include HF (heart failure) patients and nonHF controls, i.e., those without heart failure)

• Subjects will be asked to undergo steps 1-9 above, ingest 1 week of BRJ (1 "shot"/day) and then undergo the studies listed 5)-9).
• Subjects will be asked to ingest 1 more week of BRJ (1 "shot"/day for a total of 2 weeks) and then undergo a repeat of studies listed 5)-9)

For the BRJ neuromuscular function testing sub-study:

• Subjects will be asked to undergo steps 1-6 above
• Subjects will be asked to undergo a mouth swab for bacterial DNA analyses.
• Subjects will undergo a test of neuromuscular function using an isokinetic dynamometer (a device that measures voluntary muscle force production while controlling the speed of movement) immediately after the echocardiogram at ~2 h after BRJ (or placebo ingestion).

3A) Subjects will be asked to undergo an optional skeletal muscle biopsy immediately after the Biodex study.

3B) Subjects will undergo a dual-energy isokinetic dynamometry study for body composition analysis (at any time point during the study day).

• Subjects will undergo a 7 d washout period.

• Subjects will come in for Study day 2 in which they will receive whichever treatment (BRJ or placebo) they did not receive at first and then repeat the studies listed above 1-3.

For the Pulmonary artery (PA) pressure sub-study:

NOTE: This study will only be performed in patients who are undergoing a PA catheter placement for clinical purposes (high PA pressures) anyway.

• After consenting to participate, subjects will be instructed to refrain from spitting or the use of an antibacterial mouthwash, antacids, proton pump inhibitors, or chewing gum during the study.
• Subjects will be asked to answer questionnaires regarding their medical health (basic health questionnaire, Minnesota living with heart failure questionnaire, etc.) 2a) Subjects will be asked to undergo a physical examination.
• Before and at 3 (hourly) time points after receiving a "shot" of BRJ, subjects will undergo phlebotomy for plasma nutrient/hormone levels and will have their blood pressure checked and will blow into a tube connected to a small machine that will measure the amount of nitric oxide in their breath. Subjects will also have cardiovascular measurements (e.g., cardiac output, PA pressure, etc.) made before and at 3 ~ hourly time points after receiving the BRJ. These measurements will be made using a PA catheter that is being placed for clinical purposes.
• If a subject is to undergo an LVAD placement he/she will be randomized to receive BRJ or placebo the evening before surgery (anticipated average ~ 8-12 hours before), and then the LV core will be harvested and immediately frozen for later analysis.
• Subjects who will be undergoing myocardial perfusion studies will undergo the same basic studies (breath NO, plasma nitrate/nitrite determination, as mentioned in the neuromuscular aim, but subjects will also undergo a positron emission tomography (PET) study in which they will receive O-15 water for quantification of myocardial blood flow ~ 2 hours after consumption of BRJ or placebo. Then they will undergo a washout phase of 7 d and then repeat the PET study after the other treatment (BRJ or placebo).

Inclusion criteria

• Men and women will have a history of heart failure (and/or pulmonary hypertension for PA catheter substudy).
• Age > or = 18 y and controls of the same age range without heart failure.

Exclusion criteria

• Age < 18 y.
• Those taking phosphodiesterase inhibitors (e.g., Viagra) will be excluded, as these can potentiate NO effects.
• Those taking proton pump inhibitors, antacids, or xanthine oxidase inhibitors will be excluded as these can affect reduction of nitrate (NO3-) and nitrite (NO2-) to nitric oxide (NO).