Evidence suggests that the peak skeletal muscle mitochondrial ATP synthesis rate ( V) in patients with peripheral artery disease (PAD) may be attenuated due to disease-related impairments in O supply. However, in vitro assessments suggest intrinsic deficits in mitochondrial respiration despite ample O availability. To address this conundrum, Doppler ultrasound, near-infrared spectroscopy, phosphorus magnetic resonance spectroscopy, and high-resolution respirometry were combined to assess convective O delivery, tissue oxygenation, V, and skeletal muscle mitochondrial capacity (complex I + II, state 3 respiration), respectively, in the gastrocnemius muscle of 10 patients with early stage PAD and 11 physical activity-matched healthy control (HC) subjects. All participants were studied in free-flow control conditions (FF) and with reactive hyperemia (RH) induced by a period of brief ischemia during the last 30 s of submaximal plantar flexion exercise. Patients with PAD repeated the FF and RH trials under hyperoxic conditions (FF + 100% O and RH + 100% O). Compared with HC subjects, patients with PAD exhibited attenuated O delivery at the same absolute work rate and attenuated tissue reoxygenation and V after relative intensity-matched exercise. Compared with the FF condition, only RH + 100% O significantly increased convective O delivery (~44%), tissue reoxygenation (~54%), and V (~60%) in patients with PAD ( P < 0.05), such that V was now not different from HC subjects. Furthermore, there was no evidence of an intrinsic mitochondrial deficit in PAD, as assessed in vitro with adequate O. Thus, in combination, this comprehensive in vivo and in vitro investigation implicates O supply as the predominant factor limiting mitochondrial oxidative capacity in early stage PAD. NEW & NOTEWORTHY Currently, there is little accord as to the role of O availability and mitochondrial function in the skeletal muscle dysfunction associated with peripheral artery disease. This is the first study to comprehensively use both in vivo and in vitro approaches to document that the skeletal muscle dysfunction associated with early stage peripheral artery disease is predominantly a consequence of limited O supply and not the impact of an intrinsic mitochondrial defect in this pathology.

Objective Nicotinic acid (a.k.a. niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment due to a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response upon consumption of spicy food. Approach and Results We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1−/− knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at sub-millimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. Activation of TRPV1 by voltage or ligands (capsaicin and 2-APB) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-APB activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and improve compliance.

Background One of the many unique features of heart failure with preserved ejection fraction (HFpEF) is the presence of multiple comorbidities, many of which are characterized by a pro‐inflammatory and pro‐oxidant state which may impair vascular function. This axis of inflammation, oxidative stress, and vascular function has been well described in other patient populations, whereby increases in reactive oxygen species lead to eNOS uncoupling, reduced nitric oxide (NO) bioavailability, and ultimately, impaired endothelium‐dependent vasodilation. Though there are many potential strategies for combating the damaging effects of inflammation and oxidative stress on peripheral vascular function, antioxidant (AO) administration has emerged as a simple, but effective, approach. However, no studies to date have evaluated the efficacy of AO administration to target peripheral vascular inflammation and dysfunction in patients with HFpEF. Purpose The present study sought to evaluate the efficacy of an over‐the‐counter antioxidant (AO) cocktail (600mg alpha lipoic acid, 1,000mg vitamin C, and 600IU vitamin E) to acutely mitigate inflammation and oxidative stress, and subsequently improve vascular function, in patients with HFpEF. Methods Flow mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit vessel and microvascular function, respectively, following administration of either placebo (PL) or AO in 16 HFpEF patients (73±10yrs) using a double‐blind, crossover design. Circulating biomarkers of inflammation (C‐reactive protein, CRP), oxidative stress (Malondialdehyde and Protein Carbonyl), free radical concentration (EPR Spectroscopy), antioxidant capacity, and nitric oxide (NO) bioavailability (plasma nitrate, NO3− and nitrite, NO2−) were also assessed. Results FMD improved following AO administration (PL: 3.49 ± 0.7%, AO: 5.83 ± 1.0%), while RH responses were similar between conditions (PL: 428 ± 51ml, AO: 425 ± 51ml). AO administration decreased CRP (PL: 4429 ± 705ng/ml, AO: 3664 ± 520ng/ml) and increased NO2− (PL: 182 ± 21nM, AO: 213 ± 24nM), but did not affect other biomarkers. Conclusions This study has identified the efficacy of an acute, over‐the‐counter dose of vitamins C, E, and alpha lipoic acid to mitigate vascular inflammation and improve conduit artery endothelium‐dependent vasodilation in patients with HFpEF, providing new insight into the mechanisms that govern peripheral vascular dysfunction in this patient group. Support or Funding Information Funded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001311, RX001697, CX001183). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.