BEET root juice to reverse functional impairment in PAD: The BEET PAD Trial

Our work and that of others demonstrate that people with lower extremity peripheral artery disease (PAD) have greater functional impairment, more rapid functional decline, and faster mobility loss than those without PAD. In PAD, lower extremity ischemia during walking activity increases gastrocnemius (calf) muscle oxidative stress, damages myofibers, and induces calf muscle mitochondrial dysfunction. Yet few medical therapies improve functional impairment or prevent mobility loss in PAD. Inorganic nitrate, abundant in beetroot juice, is a major source of nitric oxide (NO). In preclinical studies, NO increases angiogenesis and perfusion, protects against ischemic injury, enhances mitochondrial activity, and activates satellite cells, which restore and repair skeletal muscle. In three small pilot clinical trials, including two by our co-investigator Dr. Jason Allen, oral nitrate or beetroot juice meaningfully improved walking ability in people with PAD, compared to placebo. We propose a definitive multi-centered double-blind randomized trial of beetroot juice vs. placebo in 210 people with PAD. We hypothesize that by increasing lower extremity perfusion, calf muscle mitochondrial activity, and myofiber health and regeneration, beetroot juice will improve walking performance in PAD. Our primary aim will determine whether, compared to placebo, beetroot juice significantly improves six-minute walk at 4-month follow-up. In secondary aims, we will distinguish acute from chronic effects of beetroot juice on six-minute walk and measure the effects of beetroot juice on calf muscle perfusion, brachial artery flow-mediated dilation, physical activity (ActiGraph), the Walking Impairment Questionnaire, and the short physical performance battery (SPPB). Nitrate in beetroot juice is metabolized to nitrite and subsequently to NO, attaining peak nitrite levels 2.5 hours after ingestion. Inter-individual variability exists in the extent of metabolic conversion of nitrate to nitrite. Therefore, in a secondary aim, among PAD participants randomized to beetroot juice, we will determine whether those who attain a higher peak or a greater increase in plasma nitrite 2.5 hours after beetroot juice consumption have greater increases in six-minute walk at 4-month follow-up, compared to those who attain a lower peak or a smaller increase in plasma nitrite. We will also measure the durability of beetroot juice effects, by repeating six-minute walk distance 7 and 14 days after the final dose of beetroot juice or placebo. We will perform calf muscle biopsy at baseline and follow-up to study the effects of beetroot juice on muscle mitochondrial biogenesis and activity, mitophagy, capillary characteristics, and myofiber health. If beetroot juice improves functional performance and prevents functional decline in PAD, this widely available and well tolerated therapy will have a major impact on preventing mobility loss and improving quality of life in the large and growing number of people disabled by PAD.