Impaired microcirculatory function, mitochondrial respiration, and oxygen utilization in skeletal muscle of claudicating patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs blood flow and muscle function in the lower limbs. A skeletal muscle myopathy characterized by mitochondrial dysfunction and oxidative damage is present in PAD; however, the underlying mechanisms are not well established. We investigated the impact of chronic ischemia on skeletal muscle microcirculatory function and its association with leg skeletal muscle mitochondrial function and oxygen delivery and utilization capacity in PAD. Gastrocnemius samples and arterioles were harvested from patients with PAD (n = 10) and age-matched controls (Con, n = 11). Endothelium-dependent and independent vasodilation was assessed in response to flow (30 µL·min-1), acetylcholine, and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiration was quantified by high-resolution respirometry, microvascular oxygen delivery, and utilization capacity (tissue oxygenation index, TOI) were assessed by near-infrared spectroscopy. Vasodilation was attenuated in PAD (P < 0.05) in response to acetylcholine (Con: 71.1 ± 11.1%, PAD: 45.7 ± 18.1%) and flow (Con: 46.6 ± 20.1%, PAD: 29.3 ± 10.5%) but not SNP (P = 0.30). Complex I + II state 3 respiration (P < 0.01) and TOI recovery rate were impaired in PAD (P < 0.05). Both flow and acetylcholine-mediated vasodilation were positively associated with complex I + II state 3 respiration (r = 0.5 and r = 0.5, respectively, P < 0.05). Flow-mediated vasodilation and complex I + II state 3 respiration were positively associated with TOI recovery rate (r = 0.8 and r = 0.7, respectively, P < 0.05). These findings suggest that chronic ischemia attenuates skeletal muscle arteriole endothelial function, which may be a key mediator for mitochondrial and microcirculatory dysfunction in the PAD leg skeletal muscle. Targeting microvascular dysfunction may be an effective strategy to prevent and/or reverse disease progression in PAD.NEW & NOTEWORTHY Ex vivo skeletal muscle arteriole endothelial function is impaired in claudicating patients with PAD, and this is associated with attenuated skeletal muscle mitochondrial respiration. In vivo skeletal muscle oxygen delivery and utilization capacity is compromised in PAD, and this may be due to microcirculatory and mitochondrial dysfunction. These results suggest that targeting skeletal muscle arteriole function may lead to improvements in skeletal muscle mitochondrial respiration and oxygen delivery and utilization capacity in claudicating patients with PAD.

Effects of passive and active leg movements to interrupt sitting in mild hypercapnia on cardiovascular function in healthy adults.

Prolonged sitting in a mild hypercapnic environment impairs peripheral vascular function. The effects of sitting interruptions using passive or active skeletal muscle contractions are still unclear. Therefore, we sought to examine the vascular effects of brief periods (2 min every half hour) of passive and active lower limb movement to interrupt prolonged sitting with mild hypercapnia in adults. Fourteen healthy adults (24 ± 2 yr) participated in three experimental visits sitting for 2.5 h in a mild hypercapnic environment (CO2 = 1,500 ppm): control (CON, no limb movement), passive lower limb movement (PASS), and active lower limb movement (ACT) during sitting. At all visits, brachial and popliteal artery flow-mediated dilation (FMD), microvascular function, plasmatic levels of nitrate/nitrite and endothelin-1, and heart rate variability were assessed before and after sitting. Brachial and popliteal artery FMDs were reduced in CON and PASS (P < 0.05) but were preserved (P > 0.05) in ACT. Microvascular function was blunted in CON (P < 0.05) but was preserved in PASS and ACT (P > 0.05). In addition, total plasma nitrate/nitrite was preserved in ACT (P > 0.05) but was reduced in CON and PASS (P < 0.05), and endothelin-1 levels were decreased in ACT (P < 0.05). Both passive and active movement induced a greater ratio between the low-frequency and high-frequency bands for heart rate variability (P < 0.05). For the first time, to our knowledge, we found that brief periods of passive leg movement can preserve microvascular function, but that an intervention that elicits larger increases in shear rate, such as low-intensity exercise, is required to fully protect both macrovascular and microvascular function and circulating vasoactive substance balance.NEW & NOTEWORTHY Passive leg movement could not preserve macrovascular endothelial function, whereas active leg movement could protect endothelial function. Attenuated microvascular function can be salvaged by passive movement and active movement. Preservation of macrovascular hemodynamics and plasma total nitrate/nitrite and endothelin-1 during prolonged sitting requires active movement. These findings dissociate the impacts induced by mechanical stress (passive movement) from the change in metabolism (active movement) on the vasculature during prolonged sitting in a mild hypercapnic environment.

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 µM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease.

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.

Impacts of prolonged sitting with mild hypercapnia on vascular and autonomic function in healthy recreationally active adults.

Prolonged sitting, which is known to impair peripheral vascular function, often occurs in spaces (e.g., offices) with mild hypercapnic atmospheres. However, the effects of prolonged sitting in hypercapnic conditions on vascular function are unknown. Therefore, the purpose of this study was to investigate the effects of prolonged sitting in mild hypercapnic conditions on vascular and autonomic function in humans. Twelve healthy young adults participated in two experimental visits that consisted of sitting for 2.5 h in a control condition [normal atmospheric conditions sitting (PSIT)] or a mild hypercapnic condition (HCAP; CO2 = 1,500 ppm). During each visit, heart rate variability (HRV), blood pressure (BP), pulse wave velocity (PWV), augmentation index (AIx), brachial and popliteal artery flow-mediated dilation (FMD), and near-infrared spectroscopy (NIRS) were assessed before and after prolonged sitting. Sitting significantly decreased AIx in both groups (P < 0.05). Brachial and popliteal FMD were reduced with sitting (P < 0.05), and the reduction in popliteal FMD was amplified by HCAP (P < 0.05). Baseline microvascular oxygenation was decreased following sitting in both groups (P < 0.05). However, microvascular reoxygenation upon cuff release was slower only in HCAP (P < 0.05). HRV, HR, BP, and PWV did not significantly change with sitting in either group (P > 0.05). We conclude that prolonged sitting attenuated both brachial and popliteal endothelial function and was associated with perturbed microcirculation. Additionally, mild hypercapnic conditions further impaired peripheral endothelial and microvascular function. Together, these findings suggest that prolonged sitting is accompanied by a host of deleterious effects on the vasculature, which are exacerbated by mild hypercapnia.NEW & NOTEWORTHY The results of this study reveal that prolonged sitting attenuates endothelial function and microvascular function. Additionally, prolonged sitting with mild hypercapnia, which is similar to everyday environments, further exacerbates peripheral endothelial function and microvascular function.