Beet the Best?

Abstract

Rationale A primary goal of therapy for patients with peripheral arterial disease and intermittent claudication (PAD+IC) is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions. Objective To determine whether a 36-session exercise rehabilitation program while consuming oral inorganic nitrate (4.2mmol concentrated beetroot juice- EX+BR) would produce superior benefits over exercise plus placebo (EX+PL) in pain free walking and markers of increased skeletal muscle perfusion in patients with PAD+IC. Methods and Results This was a randomized, double-blind, per-protocol study design. Following the 12-week protocol claudication onset time (COT) on a maximal treadmill test increased by 59.2±57.3 sec for the EX+PL group (n=13), and by 180.3±46.6 sec for the EX+BR group (n=11) (p≤0.05). This produced a between treatment medium to large standardized effect size (Cohen’s d) of 0.62 (95%CI = −0.23 to +1.44). The data for six minute walk (6MW) distance showed a similar pattern with increases of 24.6±12.1 m and 53.3±19.6 m (p≤0.05) in the EX+PL and EX+BR groups respectively. Measures of gastrocnemius perfusion including ABI, peak reactive hyperemic blood flow and tissue deoxygenation characteristics during exercise (assessed my near infra-red spectroscopy) all changed significantly for the EX+BR group with moderate to large effect sizes over EX+PL changes. Conclusions While it is premature to speculate on overall clinical utility of a nitrate based therapy for PAD, this early pilot study evidence is encouraging. Specifically, our data suggests that increasing plasma nitrite prior to exercise may allow PAD subjects to train with less pain, at higher workloads for longer durations at each training session thereby maximizing the beneficial peripheral vascular and skeletal muscle adaptations. Clinical Trial Registration (NCT01684930, NCT01785524).

Acute Dietary Nitrate Supplementation Improves Flow Mediated Dilatation of the Superficial Femoral Artery in Healthy Older Males

“…Our interest in the impact of NO 3 − supplementation on vascular function in the leg began with the observation that NO 3 − supplementation was associated with a decrease in blood pressure [62] and an improvement in exercise tolerance in older adults [22], and in patients with peripheral arterial disease [23,24], heart failure with preserved ejection fraction [47], and stable angina [63]. It was proposed that dietary NO 3 − may enhance plasma NO 2 − , which may increase NO bioavailability [31].…”

“…Reduction of NO 2 − to NO is facilitated in ischemic conditions [19,21], suggesting that this pathway of NO generation may protect the tissues from metabolic stress. Inorganic NO 3 − supplements, such as concentrated beetroot juice, have been shown to acutely improve exercise tolerance in older adults [22] and in patients with peripheral arterial disease [23,24]. Vascular mechanisms may contribute to this enhancement in exercise tolerance [25,26], as NO 3 − supplements have been shown to induce a temporary reduction in blood pressure [27] and arterial stiffness [28,29,30] in older adults.…”

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

“…After 10 weeks of twice-daily supplementation with NaNO 2 (40 or 80 mg) versus placebo in diabetic patients with PAD, there was an improvement in endothelial function in these patients with nitrite treatment, but there was no effect on 6-minute walk time (Mohler et al, 2014). Conversely, 8 weeks of NaNO 3 (8.5 mmol/day nitrate) was associated with a ;40 m improvement in the 6-minute walk test (Bock et al, 2018a), although there was only a trend for similar effect (;30 m) after 12 weeks of 4.2 mmol nitrate with a structured exercise program compared with exercise and placebo (Woessner et al, 2018). However, these effects may have been explained, despite randomization and blinding, by a slightly worse baseline in the nitratetreated group and thus greater apparent improvement.…”

The Effect of Dietary Inorganic Nitrate Supplementation on Cardiac Function during Submaximal Exercise in Men with Heart Failure with Reduced Ejection Fraction (HFrEF): A Pilot Study

“…Inorganic nitrate supplementation is an established intervention for increasing NO bioavailability in both healthy and diseased populations [11,12]. While previous studies have demonstrated improvements in exercise performance and vascular outcomes in diverse clinical cohorts, the majority of studies in HFrEF have indicated that supplementation has a minimal effect [13][14][15][16] However, evidence in HFpEF suggests the potential for nitrate (and nitrite) supplementation to improve systemic vascular resistance (SVR) and cardiac output (CO) [10,17]. To our knowledge, no study to date has examined the effects of supplementation on measures of cardiac function during exercise.…”