Dietary Nitrate for Heart Failure

Overview

The purpose of this study is to determine if nitrates in a food, in this case - beetroot juice (BRJ) - is efficacious in improving exercise tolerance and/or peak power in patients with heart failure. The investigators will also determine if BRJ improves blood pressure, exercise efficiency, vascular and muscle function, and whether blood levels of nitrates increase hourly for a total of 4 hours after BRJ ingestion. A secondary aim is to determine if BRJ-derived nitrates are still effective at 1, 2 and 4 weeks after starting treatment. A tertiary aim is to determine the variation in the 6 minute walk test. Subjects will answer a basic medical information sheet and undergo a 6-minute walk test. After at least a 48 hours rest, subjects will be asked to repeat the 6 minutes' walk. The investigators will (1) determine if BRJ (as compared to placebo) improves peak power output in heart failure patients and controls (at \~ 1½ to 2 hours after ingestion); (2) compare the changes in cardiac muscle (on average \~ 8-12 hours after) BRJ or placebo ingestion in patients who will be undergoing an left ventricle (LV) assist device placement for clinical purposes. (a cross-sectional study); (3) determine if BRJ decreases elevated pulmonary artery (PA) pressures or improves vascular and/or microvascular function (at \~ 1½ - 2 hours after ingestion) in patients who are already coming in for a PA catheter placement for clinical purposes; (4) compare the physiological changes after BRJ ingestion in non-heart failure control subjects with those of patients with heart failure. Endpoints measured at the same time points after ingestion. The investigators hypothesize (1) that patients with heart failure and controls will have improved exercise capacity and power at lower oxygen cost (and thereby greater efficiency) \~ 1½- 2 hours after ingesting beet juice (BRJ) than after ingesting placebo (beet juice without nitrates); (2) that patients with heart failure will have a greater physiologic response to BRJ than non-heart failure controls since the former have worse physiological function to start with; (3) that patients with high pulmonary artery pressures will have an improvement in the pressures after ingestion with BRJ; (4) that myocardial perfusion will be higher after BRJ ingestion than after placebo; (5) that cyclic guanosine monophosphate (cGMP) levels will be increased in left ventricle assist device (LVAD) samples after BRJ ingestion compared with placebo.

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): 1. 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. 2. 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. 3. Subjects will be interviewed by a dietician with regards to their typical dietary intake and instructed on a low nitrate diet. 4. In study visit #1 subjects will be randomized to receive either a "shot" of BRJ (James White Drinks)or placebo (BRJ without nitrates). 5. 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. 6. \~ 1 3/4 hours after ingestion, subjects will undergo a 6 minute walk. 7. \~ 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. 8. 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. 9. 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) 10. Subjects will undergo a 7 d wash-out period 11. 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) 1. 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). 2. 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: 1. Subjects will be asked to undergo steps 1-6 above 2. Subjects will be asked to undergo a mouth swab for bacterial DNA analyses. 3. 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). 4\) Subjects will undergo a 7 d washout period. 5\) 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. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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).