“Beet It”
2018; Lippincott Williams & Wilkins; Volume: 123; Issue: 6 Linguagem: Holandês
10.1161/circresaha.118.313667
ISSN1524-4571
Autores Tópico(s)Antioxidant Activity and Oxidative Stress
ResumoHomeCirculation ResearchVol. 123, No. 6"Beet It" Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUB"Beet It" Jay H. Traverse Jay H. TraverseJay H. Traverse Correspondence to Jay H. Traverse, MD, Cardiovascular Division, Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, University of Minnesota School of Medicine, 920 E 28th St, Suite 300, Minneapolis, MN 55407. Email E-mail Address: [email protected] From the Cardiovascular Division, Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, University of Minnesota School of Medicine. Originally published30 Aug 2018https://doi.org/10.1161/CIRCRESAHA.118.313667Circulation Research. 2018;123:635–637This article is a commentary on the followingBeet the Best?Consumers are inundated with information and advertising for dietary supplements. In response, they have created a rapidly growing market estimated in value at $133 billion in 2016. With projected annual growth of ≈10%, this market is projected to reach $278 billion by 2024 (Grand View Research Inc, San Francisco, CA). Supplements are touted to do many things: reduce free radicals and aging or enhance testosterone production or weight loss, etc. However, few of these supplements undergo rigorous placebo-controlled trials to assess their scientific merit. Indeed, a recent meta-analysis found no clinical benefit for patients taking multivitamins and mineral supplements on cardiovascular outcomes.1Article, see p 654However, some supplements have been studied in depth and may have cardiovascular benefits. The dietary supplement beetroot juice (BRJ) contains high quantities of nitrate (Figure). Once thought as an inert byproduct of nitric oxide (NO) metabolism, nitrate and nitrite are now thought to be circulating reservoirs of stored NO. Nitrate is rapidly absorbed in the gut and circulates in the plasma. Circulating nitrate is actively taken up by the salivary glands and secreted in saliva where it is converted to nitrite by oral facultative bacteria in the deep crypts of dorsal surface of the tongue. This nitrite-rich saliva is absorbed in the stomach where the low pH favors its conversion back to NO or absorbed into the circulation where it may be converted to NO via a variety of enzymatic processes that reduces nitrite to NO.2 Acute ingestion of BRJ or inorganic nitrate results in significant increases in plasma levels of nitrite that peaks within 3 hours3 or as exhaled NO that can be measured within 60 minutes of nitrate ingestion.4Download figureDownload PowerPointFigure. Commercially available superconcentrated beet juice powder.BRJ has been found to enhance athletic performance and endurance in a variety of activities, such as cycling, rowing, and running. Bailey et al5 first reported the use of BRJ as a nitrate donor in normotensive young adult men (26±7 years) undergoing submaximal cycling exercise. There it was found to double plasma nitrite levels, reduce systolic blood pressure, improve muscle oxygenation, and result in a significant 20% reduction in the oxygen cost of cycling exercise, suggesting an effect on cellular metabolism. Hobbs et al2 randomized healthy subjects to increasing doses of BRJ (0–500 g) and observed dose-dependent decreases in systolic and diastolic blood pressure that peaked 2 to 3 hours postingestion. Urinary NOx concentrations that reflected systemic NO production increased in proportion to the decline in blood pressure. Muggeridge et al6 administered a single dose of BRJ (70 mL=5 mmol nitrate) to cyclists before performing submaximal exercise and time trials at moderate simulated altitude (2500 m). BRJ increased plasma nitrite from 39.1 to 150.5 μmol/L and decreased Vo2 during steady-state exercise (2542 versus 2727 mL/min versus placebo) while improving their time trial. Although not every study using BRJ has improved exercise performance, the majority of studies suggest that the resultant increase in plasma nitrite levels after BRJ ingestion may be of cardiovascular benefit.7Subjects with peripheral arterial disease (PAD) and claudication may be an ideal cohort to benefit from increasing nitrite levels with BRJ as the conversion of nitrite to NO is enhanced in the relatively ischemic environment that arises from hypoperfusion.8 Compared with normal controls, subjects with PAD experience a decline in plasma levels of nitrite after exercise,9 consistent with the findings that NO production is impaired as a result of endothelial dysfunction and that the conversion of nitrite to NO is enhanced in the setting of low oxygen tension. In the ischemic hind-limb mouse model,10 increasing doses of sodium nitrite administered daily increased vascular density and hind-limb blood flow over 3 to 7 days and increased endothelial cell proliferation, which was abolished in the presence of an NO scavenger. Importantly, no effect on blood flow in the contralateral nonischemic limb was observed.However, the pathophysiology of claudication is more than just endothelial dysfunction and impaired tissue perfusion from arterial obstruction as cellular and mitochondrial energetics are also impaired independent of blood flow. Anderson et al11 observed that the phosphocreatine recovery time constant in the calf muscle of claudicants failed to correlate with measurements of calf perfusion. Similarly, patients undergoing a 12-week exercise program experience significant improvements in exercise duration that was related to improved cellular metabolism (carnitine) but not to blood flow. Thus, by 12 weeks, subjects demonstrated an increase in peak Vo2, suggesting improved oxygen delivery or oxidative metabolism.12 Given NO's known effect on mitochondrial energetics, this may represent an additional pathway for the benefit of nitrate/nitrite to act in addition to improving endothelial function and hypoxic vasodilation.Having previously demonstrated that changes in plasma nitrite levels and endothelial function were the most important predictors of exercise performance in subjects with PAD, Kenjale et al3 was the first to examine if dietary supplementation of nitrate with BRJ would improve exercise capacity in this cohort. They observed that 500 mL of BRJ resulted in a 6-fold increase in plasma nitrite levels in 3 hours after ingestion, increased claudication onset time by 18% and peak walking time by 17% during a maximal cardiopulmonary stress test. Skeletal muscle (gastrocnemius) oxygen extraction was reduced during exercise by near-infrared spectroscopy, suggesting improved mitochondrial usage of oxygen. This is supported by findings in normal subjects administered nitrate for 3 days where exercise results in a significant decline in oxygen consumption secondary to improved efficiency of oxidative phosphorylation in mitochondria isolated by skeletal muscle biopsy.13Supervised exercise represents an effective strategy to improve exercise capacity in subjects with PAD and was recently approved for reimbursement in the United States by the Centers for Medicaid and Medicare Services. The benefits of exercise are multifactorial and may include improved endothelial function and mitochondrial energetics, as well as reducing inflammation and generation of reactive oxygen species. Allen et al9 demonstrated that subjects with PAD (ankle brachial index [ABI]=0.66) who underwent supervised exercise program for 3 months experienced increase in claudication onset time (66%) and peak walking time (52%). These findings were not associated with a change in ABI, but with improved indices of endothelial function as measured by brachial artery flow-mediated dilation and a restoration of the nitrite flux, which seems highly correlated with a subjects' exercise capacity.In this issue of Circulation Research, Woessner et al14 present their findings of a small clinical trial of 24 patients with PAD and intermittent claudication that tested the hypothesis that BRJ (nitrate) in conjunction with a supervised exercise program (n=11) would improve exercise capacity and delay onset of pain compared with exercise alone (n=13). This is the first clinical trial to examine the effects of both interventions together in the same cohort of subjects and could provide further insight into the mechanisms of benefit of these interventions on exercise time and endothelial function. Enrolled subjects were required to have a reduced ABI (<0.9) and claudication as a limiting factor of exercise capacity. Subjects randomized to BRJ ingested the equivalent of 4.2 mmol No3−, 3 hours before onset of exercise as part of a 36-session program over 12 weeks. At each session, subjects exercised for at least 30 minutes excluding rest periods to allow for resolution of claudication. As anticipated, subjects in both groups experienced significant improvements in claudication onset time and 6 MW after 12 weeks of exercise. However, those subjects randomized to BRJ had a 3-fold greater improvement in exercise duration compared with the control exercise group. These improvements are even more striking given that there were significantly more subjects with diabetes mellitus in the exercise+BRJ group (6 versus 2), since the presence of subjects with diabetes mellitus is associated with reduced endothelial function and claudication onset time compared with subjects without diabetes mellitus and PAD.15Tissue oxygenation assessed with near-infrared spectroscopy was utilized to monitor gastrocnemius perfusion during the pretreatment and posttreatment exercise session. Parameters of tissue oxygenation increased in both groups over 12 weeks of training, but the improvement was significantly greater in the subjects randomized to BRJ. Additionally, the BRJ group experienced a blunting of the initial hemoglobin desaturation rate with exercise over time which was not seen in the exercise-only group. The exercise+BRJ also demonstrated a greater increase in peak reactive hyperemia after 5-minute thigh occlusion that did not occur in the exercise+placebo group, although this may have been because of the small sample size.9 Additionally, ABIs were significantly improved at the end of 12 weeks in the exercise+BRJ group, suggesting that structural changes may have occurred in the vasculature, such as enhanced collateralization as observed in the ischemic rat hind-limb model.10Although this well-conducted study was underpowered, it suggests that nitrate supplementation with BRJ provides additional functional benefits to patients with PAD, above which can be achieved with supervised exercise. This promising strategy needs to be confirmed in a much larger clinical trial along with studies to explore if the acute benefits of nitrate supplementation can be maintained with chronic administration. If confirmed, the strategy of providing nitrate supplementation to our PAD patients will be tough to BEET!DisclosuresNone.Sources of FundingThis study was supported by grants 5UM1 HL087318.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Jay H. Traverse, MD, Cardiovascular Division, Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, University of Minnesota School of Medicine, 920 E 28th St, Suite 300, Minneapolis, MN 55407. Email [email protected]eduReferences1. Kim J, Choi J, Kwon SY, McEvoy JW, Blaha MJ, Blumenthal RS, Guallar E, Zhao D, Michos ED. Association of multivitamin and mineral supplementation and risk of cardiovascular disease: a systematic review and meta-analysis.Circ Cardiovasc Qual Outcomes. 2018; 11:e004224. doi: 10.1161/CIRCOUTCOMES.117.004224LinkGoogle Scholar2. Hobbs DA, Kaffa N, George TW, Methven L, Lovegrove JA. Blood pressure-lowering effects of beetroot juice and novel beetroot-enriched bread products in normotensive male subjects.Br J Nutr. 2012; 108:2066–2074. doi: 10.1017/S0007114512000190CrossrefMedlineGoogle Scholar3. Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL, Vanbruggen M, Privette G, Yim E, Kraus WE, Allen JD. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease.J Appl Physiol (1985). 2011; 110:1582–1591. doi: 10.1152/japplphysiol.00071.2011CrossrefMedlineGoogle Scholar4. Marteus H, Törnberg DC, Weitzberg E, Schedin U, Alving K. Origin of nitrite and nitrate in nasal and exhaled breath condensate and relation to nitric oxide formation.Thorax. 2005; 60:219–225. doi: 10.1136/thx.2004.030635CrossrefMedlineGoogle Scholar5. Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ, Wilkerson DP, Tarr J, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans.J Appl Physiol (1985). 2009; 107:1144–1155. doi: 10.1152/japplphysiol.00722.2009CrossrefMedlineGoogle Scholar6. Muggeridge DJ, Howe CC, Spendiff O, Pedlar C, James PE, Easton C. A single dose of beetroot juice enhances cycling performance in simulated altitude.Med Sci Sports Exerc. 2014; 46:143–150. doi: 10.1249/MSS.0b013e3182a1dc51CrossrefMedlineGoogle Scholar7. Dominguez R, Cuenca E, Mate-Munoz JLet al. Effects of beetroot juice supplementation on cardiorespiratory endurance in athletes. A systemic review.Nutrients. 2017: 9:E43.CrossrefMedlineGoogle Scholar8. Li H, Samouilov A, Liu X, Zweier JL. Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrite reduction. Evaluation of its role in nitric oxide generation in anoxic tissues.J Biol Chem. 2001; 276:24482–24489. doi: 10.1074/jbc.M011648200CrossrefMedlineGoogle Scholar9. Allen JD, Stabler T, Kenjale A, Ham KL, Robbins JL, Duscha BD, Dobrosielski DA, Annex BH. Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3months of exercise training.Free Radic Biol Med. 2010; 49:1138–1144. doi: 10.1016/j.freeradbiomed.2010.06.033CrossrefMedlineGoogle Scholar10. Kumar D, Branch BG, Pattillo CB, Hood J, Thoma S, Simpson S, Illum S, Arora N, Chidlow JH, Langston W, Teng X, Lefer DJ, Patel RP, Kevil CG. Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis.Proc Natl Acad Sci USA. 2008; 105:7540–7545. doi: 10.1073/pnas.0711480105CrossrefMedlineGoogle Scholar11. Anderson JD, Epstein FH, Meyer CH, Hagspiel KD, Wang H, Berr SS, Harthun NL, Weltman A, Dimaria JM, West AM, Kramer CM. Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism.J Am Coll Cardiol. 2009; 54:628–635. doi: 10.1016/j.jacc.2009.01.080CrossrefMedlineGoogle Scholar12. Hiatt WR, Regensteiner JG, Hargarten ME, Wolfel EE, Brass EP. Benefit of exercise conditioning for patients with peripheral arterial disease.Circulation. 1990; 81:602–609.LinkGoogle Scholar13. Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E. Dietary inorganic nitrate improves mitochondrial efficiency in humans.Cell Metab. 2011; 13:149–159. doi: 10.1016/j.cmet.2011.01.004CrossrefMedlineGoogle Scholar14. Woessner M, VanBruggen MD, Pieper CF, Sloane R, Kraus WE, Gow AJ, Allen JD. Beet the Best? Dietary inorganic nitrate to augment exercise training in lower extremity peripheral artery disease with intermittent claudication.Circ Res. 2018; 123:654–659. doi: 10.1161/CIRCRESAHA.118.313131LinkGoogle Scholar15. Allen JD, Stabler T, Kenjale AA, Ham KL, Robbins JL, Duscha BD, Kraus WE, Annex BH. Diabetes status differentiates endothelial function and plasma nitrite response to exercise stress in peripheral arterial disease following supervised training.J Diabetes Complications. 2014; 28:219–225. doi: 10.1016/j.jdiacomp.2013.08.002CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ismaeel A, Greathouse K, Newton N, Miserlis D, Papoutsi E, Smith R, Eidson J, Dawson D, Milner C, Widmer R, Bohannon W and Koutakis P (2021) Phytochemicals as Therapeutic Interventions in Peripheral Artery Disease, Nutrients, 10.3390/nu13072143, 13:7, (2143) Related articlesBeet the Best?Mary Woessner, et al. Circulation Research. 2018;123:654-659 August 31, 2018Vol 123, Issue 6 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.313667PMID: 30355240 Originally publishedAugust 30, 2018 Keywordsexerciseclinical trialperipheral arterial diseaseEditorialsnitric oxidePDF download Advertisement
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