Combined Dietary Nitrate and Exercise Intervention in Peripheral Artery Disease: Protocol Rationale and Design

Background: Peripheral artery disease (PAD) is caused by atherosclerotic occlusions in the legs. It affects approximately 8-12 million people in the United States alone, one-third of whom suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. Patients with IC suffer a markedly impaired quality of life and a high perception of disability. Improving pain-free walking time is a primary goal of rehabilitation in this population. Objective: The nitric oxide (NO)-PAD trial is designed to compare the effects that 12 weeks of supervised exercise training, in combination with a high inorganic nitrate-content (beetroot [BR] juice) beverage or placebo (PL) beverage, has on clinical outcomes of exercise and functional capacity in two groups of PAD+IC patients: exercise training plus beetroot (EX+BR) and exercise training plus placebo (EX+PL). The primary aims of this randomized controlled, double-blind pilot study are to determine group differences following 12 weeks of EX+BR versus EX+PL in the changes for (1) exercise capacity: pain-free walking time (claudication onset time, COT), peak walk time (PWT), and maximal exercise capacity (peak oxygen uptake, VO2peak) during a maximal-graded cardiopulmonary exercise test (max CPX) and (2) functional capacity: 6-minute walk (6MW) distance. The secondary aims will provide mechanistic insights into the exercise outcome measures and will include (1) gastrocnemius muscle oxygenation during exercise via near-infrared spectroscopy (NIRS); (2) gastrocnemius muscle angiogenesis: capillaries per unit area and per muscle fiber, and relative fraction of type I, IIa, IIb, and IId/x fibers; and (3) vascular health/function via brachial artery flow-mediated dilation, lower-limb blood flow via plethysmography, and pulse wave velocity and reflection. Methods: A total of 30 subjects between 40 and 80 years of age with PAD who are limited by IC will undergo exercise training 3 days per week for 12 weeks (ie, 36 sessions). They will be randomized to either the EX+BR or EX+PL group where participants will consume a beverage high in inorganic nitrate (4.2 mmol) or a low-nitrate placebo, respectively, 3 hours prior to each training session. Results: Data collection from this study has been completed and is in the process of analysis and write-up. While the study is too underpowered—EX+BR, n=11; EX+PL, n=13—to determine between-group differences in the primary outcomes of COT, PWT, and 6MW, preliminary observations are promising with Cohen d effect sizes of medium to large. Conclusions: Exercise training is currently the most effective therapy to increase functional capacity in PAD+IC. If the addition of inorganic nitrate to an exercise regimen elicits greater benefits, it may redefine the current standard of care for PAD+IC

Beet the Best? Dietary Inorganic Nitrate to Augment Exercise Training in Lower Extremity Peripheral Artery Disease With Intermittent Claudication

Rationale: A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication 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 (4.2 mmol concentrated beetroot juice) would produce superior benefits over exercise plus placebo in pain-free walking and markers of increased skeletal muscle perfusion in patients with PAD and intermittent claudication. Methods and Results: This was a randomized, double-blind, per-protocol study design. After the 12-week protocol, claudication onset time on a maximal treadmill test increased by 59.2±57.3 s for the exercise plus placebo group (n=13) and by 180.3±46.6 s for the exercise plus beetroot juice group (n=11; P≤0.05). This produced a between treatment medium to large standardized effect size (Cohen d) of 0.62 (95% CI, −0.23 to +1.44). The data for 6-minute walk distance showed a similar pattern with increases of 24.6±12.1 and 53.3±19.6 m (P≤0.05) in the exercise plus placebo and exercise plus beetroot juice groups, respectively. Measures of gastrocnemius perfusion, including ankle-brachial index, peak reactive hyperemic blood flow, and tissue deoxygenation characteristics, during exercise (assessed my near-infrared spectroscopy) all changed significantly for the exercise plus beetroot juice group with moderate-to-large effect sizes over exercise plus placebo changes. Conclusions: Although 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 before 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: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01684930 and NCT01785524

PRIME: A Novel Low-Mass, High-Repetition Approach to Improve Function in Older Adults

Introduction: The ability to maintain functional independence in a rapidly aging population results in an increased life expectancy without corresponding increases in health care costs. The accelerated decline in V˙O2peak after the age of 65 yr is primarily due to peripheral tissue changes rather than centrally mediated factors. The purpose of this study was to determine whether the Peripheral Remodeling through Intermittent Muscular Exercise (PRIME) approach, consisting of a low-mass, high-repetition/duration skeletal muscle focused training regimen would provide superior functional benefits in participants older than 70 yr old and at risk for losing functional independence. Methods: In this clinical trial, 107 participants were randomized to 4 wk of either standard aerobic training (AT) or PRIME (phase 1). This was followed by 8 wk of a progressive whole-body aerobic and resistance training (AT + RT) for all participants (phase 2). The major outcome measures were cardiorespiratory fitness (peak oxygen consumption [V˙O2peak]), muscular fitness (1 repetition maximal strength [1RM]), and physical function (Senior Fitness Test [SFT] scores). Results were analyzed under a per-protocol criterion. Results: Thirty-eight PRIME and 38 AT participants completed the 3-month protocols. V˙O2peak, 1RM, and SFT scores all increased significantly after 12 wk for both treatment groups (P \u3c 0.05). However, relative to AT, participants randomized to PRIME demonstrated a greater increase in V˙O2peak (2.37 + 1.83 vs 1.50 + 1.82 mL·kg−1·min−1, P \u3c 0.05), 1RM (48.52 + 27.03 vs 28.01 + 26.15 kg, P \u3c 0.01) and SFT (22.50 + 9.98 vs 18.66 + 9.60 percentile, P \u3c 0.05). Conclusions: Participants experienced greater increases in cardiorespiratory and muscular fitness and physical function when PRIME training was initiated before a combined AT + RT program. This novel exercise approach may be advantageous to individuals with other chronic disease conditions characterized by low functional capacity

A Comparison of Capillary, Venous, and Salivary Cortisol Sampling After Intense Exercise

Venipuncture is expensive, invasive, and impractical for many sport-science and clinical-based settings. Salivary free cortisol is often cited as a noninvasive practical alternative. However, when cortisol concentrations exceed the corticosteroid-binding globulin (CBG) point of 500 nmol/L, a lack of agreement between salivary and venous blood cortisol has been found. Alternatively, capillary blood may present a minimally invasive, cost-effective, and practical surrogate for determining cortisol concentration. PURPOSE: The aim of this study was to determine whether cortisol concentrations sampled from capillary blood and saliva accurately reflect those found in venous blood across a large range of concentrations after intense exercise. METHODS: Eleven healthy aerobically trained male subjects were recruited. Capillary, salivary, and venous blood samples were collected before and after (immediately and 5, 10, 15, and 20 min after) a treadmill VO(2) max test. RESULTS: Capillary and venous concentrations increased at a similar rate after exercise (Cohen d.14-.33), increasing up to 15 min postexercise before a decline was seen. Salivary cortisol values increased at a slower rate than venous and capillary cortisol but continued to increase 15 min postexercise (Cohen d .19-.47 and .09-.72, respectively). CONCLUSIONS: Capillary cortisol accurately reflects concentrations assayed from venous blood across a range of values below and above the CBG binding point. Capillary sampling provides a minimally invasive, cost-effective, practical surrogate for assessment of hypothalamic-pituitary-gland function