Beet the Best? Dietary Inorganic Nitrate to Augment Exercise Training in Lower Extremity Peripheral Artery Disease with Intermittent Claudication [New Hypotheses In Clinical Medicine]

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).