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. 2017 Sep 30;69:78-90.
doi: 10.1016/j.niox.2017.05.005. Epub 2017 May 23.

Effects of Supervised Exercise and Dietary Nitrate in Older Adults With Controlled Hypertension and/or Heart Failure With Preserved Ejection Fraction

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Effects of Supervised Exercise and Dietary Nitrate in Older Adults With Controlled Hypertension and/or Heart Failure With Preserved Ejection Fraction

Hossam A Shaltout et al. Nitric Oxide. .
Free PMC article

Abstract

Aerobic exercise training is an effective therapy to improve peak aerobic power (peak VO2) in individuals with hypertension (HTN, AHA/ACC class A) and heart failure patients with preserved ejection fraction (HFpEF). High nitrate containing beetroot juice (BRJ) also improves sub-maximal endurance and decreases blood pressure in both HTN and HFpEF. We hypothesized that combining an aerobic exercise and dietary nitrate intervention would result in additive or even synergistic positive effects on exercise tolerance and blood pressure in HTN or HFpEF. We report results from two pilot studies examining the effects of supervised aerobic exercise combined with dietary nitrate in patients with controlled HTN (n = 26, average age 65 ± 5 years) and in patients with HFpEF (n = 20, average age 69 ± 7 years). All patients underwent an aerobic exercise training regimen; half were randomly assigned to consume a high nitrate-containing beet juice beverage (BRJ containing 6.1 mmol nitrate for the HFpEF study consumed three times a week and 8 mmol nitrate for the HTN study consumed daily) while the other half consumed a beet juice beverage with the nitrate removed (placebo). The main result was that there was no added benefit observed for any outcomes when comparing BRJ to placebo in either HTN or HFpEF patients undergoing exercise training (p ≥ 0.14). There were within-group benefits. In the pilot study in patients with HFpEF, aerobic endurance (primary outcome), defined as the exercise time to volitional exhaustion during submaximal cycling at 75% of maximal power output, improved during exercise training within each group from baseline to end of study, 369 ± 149 s vs 520 ± 257 s (p = 0.04) for the placebo group and 384 ± 129 s vs 483 ± 258 s for the BRJ group (p = 0.15). Resting systolic blood pressure in patients with HFpEF also improved during exercise training in both groups, 136 ± 16 mm Hg vs 122 ± 3 mm Hg for the placebo group (p < 0.05) and 132 ± 12 mm Hg vs 119 ± 9 mm Hg for the BRJ group (p < 0.05). In the HTN pilot study, during a treadmill graded exercise test, peak oxygen consumption (primary outcome) did not change significantly, but time to exhaustion (also a primary outcome) improved in both groups, 504 ± 32 s vs 601 ± 38 s (p < 0.05) for the placebo group and 690 ± 38 s vs 772 ± 95 s for the BRJ group (p < 0.05) which was associated with a reduction in supine resting systolic blood pressure in BRJ group. Arterial compliance also improved during aerobic exercise training in both the HFpEF and the HTN patients for both BRJ and placebo groups. Future work is needed to determine if larger nitrate doses would provide an added benefit to supervised aerobic exercise in HTN and HFpEF patients.

Keywords: Exercise; Heart failure with preserved ejection fraction; Hypertension; Nitrate; Nitric Oxide; Nitrite.

Conflict of interest statement

Disclosures: Dr. Kim-Shapiro is listed as a co-inventor on a patent related to use of nitrite in cardiovascular conditions, and owns stock in and serves on the scientific advisory board for Beverage Operations LLC which has licensed Wake Forest University intellectual properties and thus has a financial interest in Beverage Operations LLC. Dr. Kitzman declares the following relationships: Consultant for Abbvie, GSK, Relypsa, Regeneron, Merck, Corvia Medical, and Actavis, grant funding from Novartis, and stock ownership in Gilead Sciences and Relypsa.

No other members of the writing group have conflicts of interest to declare.

Figures

Figure 1
Figure 1
For HFpEF participants, immediately following the previous study design, V5[31], all subjects were re-randomized to either 4 weeks of EX + Placebo or 4 weeks of EX + BRJ. After the 4-week intervention, subjects completed 2 follow-up visits separated by 1–4 days. Visit 6 consisted of blood pressure measurements, a blood draw, and a submaximal constant workrate exercise test. Visit 7 consisted of a resting Echo-Doppler exam and a maximal exercise test. Baseline values are from the placebo visit during the cross-over design from the previous study (either V3 or V4) or from the screening visit 1 for the Echo-Doppler and maximal exercise test outcomes only. For HTN participants, immediately following the initial screening and assessment of exercise performance, cardiovascular and autonomic function at visit 1, all subjects were randomized to either 6 weeks of EX + Placebo or 6 weeks of EX + BRJ. After 6 weeks intervention, subjects returned for follow up visit 2 where the same outcomes were measured again.
Figure 1
Figure 1
For HFpEF participants, immediately following the previous study design, V5[31], all subjects were re-randomized to either 4 weeks of EX + Placebo or 4 weeks of EX + BRJ. After the 4-week intervention, subjects completed 2 follow-up visits separated by 1–4 days. Visit 6 consisted of blood pressure measurements, a blood draw, and a submaximal constant workrate exercise test. Visit 7 consisted of a resting Echo-Doppler exam and a maximal exercise test. Baseline values are from the placebo visit during the cross-over design from the previous study (either V3 or V4) or from the screening visit 1 for the Echo-Doppler and maximal exercise test outcomes only. For HTN participants, immediately following the initial screening and assessment of exercise performance, cardiovascular and autonomic function at visit 1, all subjects were randomized to either 6 weeks of EX + Placebo or 6 weeks of EX + BRJ. After 6 weeks intervention, subjects returned for follow up visit 2 where the same outcomes were measured again.
Figure 2
Figure 2
Plasma NOx levels at baseline and following beverage consumption. (A) Nitrite from the HFpEF study. (B) Nitrate from the HFpEF study. (C) Nitrite from the HTN study. (D) Nitrate from the HTN study.
Figure 3
Figure 3
VO2 (Panel A) and Systolic Blood Pressure (Panel B) at rest, after unloaded cycling, after 2 and 4 minutes, and at volitional exhaustion (max) from the submaximal constant work rate exercise test in the HFpEF study. Values are the follow-up least square means ± SE (adjusted for the baseline values). The circles and solid line represent the EX + Placebo group and the squares and dotted line represent the EX + Beetroot juice group. There were no differences between Placebo and BRJ groups,
Figure 4
Figure 4
Effect of exercise (dark color panels) compared to baseline (light color panel) for the HTN study in subjects receiving either high nitrate beet root juice or placebo on VO2 (A); Exercise time (B); Supine systolic blood Pressure (C) Supine diastolic blood pressure (D). Data presented as mean ± SE. * = p<0.05 for follow up vs baseline within the same group, # = p<0.05 for BRJ vs placebo.
Figure 5
Figure 5
Relationship between nitrate to nitrite response to improvement in exercise time in the HTN study. Participants were broken into three groups: best responders (BR), good responders (GR), and non-responders (NR) based on change in plasma nitrite following BRJ consumption. Data are the average and standard error of the mean for improvement in exercise time.

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