EFFECTS OF NICOTINAMIDE RIBOSIDE SUPPLEMENTATION ON HEMODYNAMIC AND OXYGENATION RESPONSES DURING EXERCISE IN PERIPHERAL ARTERY DISEASE

Abstract

Peripheral Artery Disease (PAD) is characterized by reduced limb blood flow, impaired vascular conductance and reduced tissue oxygenation during exercise. Nicotinamide Riboside (NR), a precursor to Nicotinamide Adenine Dinucleotide (NAD+), may improve impaired vascular function and skeletal muscle oxygen utilization in this population. PURPOSE: The purpose of the present study was to examine the effects of NR supplementation on hemodynamic and oxygenation responses during plantar flexion exercise in participants with PAD compared to an age- and sex-matched comparison group (COMP). METHODS: Six participants with PAD (66 ± 9 y, 5F) and six COMP participants (67 ± 8 y, 5F) completed two experimental visits (PRE and POST NR supplementation). Leg blood flow (LBF, Doppler ultrasound), mean arterial pressure (MAP, finger photoplethysmography), leg vascular conductance (LVC, LBF/MAP), estimated oxygen uptake (estVO2) and muscle oxygenation (near-infrared spectroscopy: TSI, tHb, O2Hb, HHb) were assessed during rhythmic plantar flexion exercise at an intensity of 4% Body weight x Body height. Mixed-effects models and area under the curve (AUC) analyses were used to evaluate PRE to POST differences. RESULTS: AUC analysis revealed a significant PRE to POST increase in tHb (p = 0.04, d = 1.17) and O2Hb (p = 0.05, d = 1.04) in the PAD group, with very large effect sizes. TSI demonstrated a significant Group x Test interaction (p = 0.003, ηp² = 0.04), with post hoc comparisons revealing significant PRE to POST increases at select time points during exercise in PAD but not COMP. For hemodynamic variables (n = 4 per group, n = 6 in MAP), mixed-effects models revealed significant main effects of Group, Test, and Time for LBF, MAP and LVC, with post hoc comparisons identifying significant PRE to POST improvements at select time points within the COMP group. A significant three-way Group x Test x Time interaction was detected for LVC (p = 0.043), indicating that the PRE to POST change across the exercise bout differed between groups. AUC analyses did not reach significance for LBF, LVC, or estVO2 in either group, though large effect sizes in COMP (r = 0.67 - 0.77) suggest the study was underpowered to detect potentially meaningful hemodynamic adaptations. Notably, MAP AUC was significantly reduced in COMP (p = 0.01, d = 1.85). An exploratory analysis (n = 3 per group) revealed faster hemodynamic kinetic responses in PAD following NR supplementation, with tau and MRT reductions of d = 0.90 - 1.42, with no changes observed in the COMP group. CONCLUSION: Our results indicate that 28 days of NR supplementation were associated with distinct physiological improvements depending on disease state. In individuals with PAD, NR improved skeletal muscle oxygenation at the microvascular level, as suggested by tHb and O2Hb, time-point specific improvements in TSI, and faster hemodynamic response kinetics, potentially reflecting improved mitochondrial efficiency and/or capillary recruitment in chronically ischemic muscle. Conversely, healthy older adults demonstrated improvements in bulk flow hemodynamics and attenuated MAP during exercise, consistent with NR mediated rises in NO bioavailability and therefore smooth muscle relaxation. Therefore, our findings suggest NR supplementation may target human physiological mechanisms depending on the degree of metabolic and vascular impairment and establishing the clinical relevance of NR supplementation to walking capacity and quality of life in patients with PAD and intermittent claudication.