Moderate dose of dietary nitrate improves skeletal muscle microvascular function in patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease characterized by compromised lower-extremity blood flow that impairs walking ability. We showed that a moderate dose of dietary nitrate in the form of beetroot juice (BRJ, 0.11 mmol/kg) can improve macrovascular function and maximal walking distance in patients with PAD. However, its impacts on the microcirculation and autonomic nervous system have not been examined. Therefore, we investigated the impacts of this dose of dietary nitrate on skeletal muscle microvascular function and autonomic nervous system function and further related these measurements to 6-min walking distance, pain-free walking distance, and exercise recovery in patients with PAD. Patients with PAD (n = 10) ingested either BRJ or placebo in a randomized crossover design. Heart rate variability, skeletal muscle microvascular function, and 6-min walking distance were performed pre- and post-BRJ and placebo. There were significant group × time interactions (P < 0.05) for skeletal muscle microvascular function, 6-min walking distance, and exercise recovery, but no changes (P > 0.05) in heart rate variability or pain-free walking distance were noted. The BRJ group demonstrated improved skeletal muscle microvascular function (∆ 22.1 ± 7.5 %·min-1), longer 6-min walking distance (Δ 37.5 ± 9.1 m), and faster recovery post-exercise (Δ -15.3 ± 4.2 s). Furthermore, changes in skeletal muscle microvascular function were positively associated with changes in 6-min walking distance (r = 0.5) and pain-free walking distance (r = 0.6). These results suggest that a moderate dose of dietary nitrate may support microvascular function, which is related to improvements in walking distance and claudication in patients with PAD.

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.

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.

Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: a double-blind placebo-controlled randomised crossover clinical trial.

Anthocyanins and bromelain have gained significant attention due to their antioxidative and anti-inflammatory properties. Both have been shown to improve endothelial function, blood pressure (BP) and oxygen utility capacity in humans; however, the combination of these two and the impacts on endothelial function, BP, total antioxidant capacity (TAC) and oxygen utility capacity have not been previously investigated. The purpose of this study was to investigate the impacts of a combined anthocyanins and bromelain supplement (BE) on endothelial function, BP, TAC, oxygen utility capacity and fatigability in healthy adults. Healthy adults (n 18, age 24 (sd 4) years) received BE or placebo in a randomised crossover design. Brachial artery flow-mediated dilation (FMD), BP, TAC, resting heart rate, oxygen utility capacity and fatigability were measured pre- and post-BE and placebo intake. The BE group showed significantly increased FMD, reduced systolic BP and improved oxygen utility capacity compared with the placebo group (P < 0·05). Tissue saturation and oxygenated Hb significantly increased following BE intake, while deoxygenated Hb significantly decreased (P < 0·05) during exercise. Additionally, TAC was significantly increased following BE intake (P < 0·05). There were no significant differences for resting heart rate, diastolic BP or fatigability index. These results suggest that BE intake is an effective nutritional therapy for improving endothelial function, BP, TAC and oxygen utility capacity, which may be beneficial to support vascular health in humans.

Functional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle.

KEY POINTS: Nrf2 is a master regulator of endogenous cellular defences, governing the expression of more than 200 cytoprotective proteins, including a panel of antioxidant enzymes. Nrf2 plays an important role in redox haemostasis of skeletal muscle in response to the increased generation of reactive oxygen species during contraction. Employing skeletal muscle-specific transgenic mouse models with unbiased-omic approaches, we uncovered new target proteins, downstream pathways and molecular networks of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion. Based on the findings, we proposed a two-way model to understand Nrf2 function: a tonic effect through a Keap1-independent mechanism under basal conditions and an induced effect through a Keap1-dependent mechanism in response to oxidative and other stresses. ABSTRACT: Although Nrf2 has been recognized as a master regulator of cytoprotection, its functional significance remains to be completely defined. We hypothesized that proteomic/bioinformatic analyses from Nrf2-deficient or overexpressed skeletal muscle tissues will provide a broader spectrum of Nrf2 targets and downstream pathways than are currently known. To this end, we created two transgenic mouse models; the iMS-Nrf2flox/flox and iMS-Keap1flox/flox , employing which we demonstrated that selective deletion of skeletal muscle Nrf2 or Keap1 separately impaired or improved skeletal muscle function. Mass spectrometry revealed that Nrf2-KO changed expression of 114 proteins while Keap1-KO changed expression of 117 proteins with 10 proteins in common between the groups. Gene ontology analysis suggested that Nrf2 KO-changed proteins are involved in metabolism of oxidoreduction coenzymes, purine ribonucleoside triphosphate, ATP and propanoate, which are considered as the basal function of Nrf2, while Keap1 KO-changed proteins are involved in cellular detoxification, NADP metabolism, glutathione metabolism and the electron transport chain, which belong to the induced effect of Nrf2. Canonical pathway analysis suggested that Keap1-KO activated four pathways, whereas Nrf2-KO did not. Ingenuity pathway analysis further revealed that Nrf2-KO and Keap1-KO impacted different signal proteins and functions. Finally, we validated the proteomic and bioinformatics data by analysing glutathione metabolism and mitochondrial function. In conclusion, we found that Nrf2-targeted proteins are assigned to two groups: one mediates the tonic effects evoked by a low level of Nrf2 at basal condition; the other is responsible for the inducible effects evoked by a surge of Nrf2 that is dependent on a Keap1 mechanism.

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.

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.

Correction to: The effects of a 12-week jump rope exercise program on abdominal adiposity, vasoactive substances, inflammation, and vascular function in adolescent girls with prehypertension.

The Following error was published on page 578. The incorrect IRB number under "Participants" section was accidently reported.

The effects of a 12-week jump rope exercise program on abdominal adiposity, vasoactive substances, inflammation, and vascular function in adolescent girls with prehypertension.

INTRODUCTION: Childhood obesity is strongly associated with cardiovascular disease (CVD) development. It is necessary to combat unfavorable outcomes of obesity at a young age by utilizing effective interventions, such as exercise. PURPOSE: We sought to examine the effects of a jump rope exercise program on CVD risk factors, including body composition, vasoactive substances, inflammation, and vascular function in prehypertensive adolescent girls. METHODS: Forty girls (age 14-16) were recruited and randomly assigned to a jump rope exercise group (EX, n = 20) or control group (CON, n = 20). Body composition, nitrate and nitrite levels, endothelin-1 (ET-1), C-reactive protein (CRP), systolic blood pressure and diastolic blood pressure (SBP, DBP), and arterial stiffness were measured before and after 12 weeks. RESULTS: There were significant group by time interactions following the 12-week program for body composition (from 33.8 ± 3.6 to 30.2 ± 3.1%), central adiposity (from 86.4 ± 4 to 83.3 ± 5 cm), SBP (from 126 ± 3.3 to 120 ± 2.1 mmHg), and brachial-to-ankle pulse wave velocity (from 8.2 ± 1.0 to 7.4 ± 0.2 m/s). Nitrate/nitrite levels increased (from 54.5 ± 5.1 to 57.2 ± 5.2 µmol) along a reduction in CRP levels (from 0.5 ± 0.4 to 0.2 ± 0.1 mg/L). There were no significant changes in ET-1 (P = 0.22). CONCLUSIONS: These findings indicate that jump rope exercise may be an effective intervention to improve these CVD risk factors in prehypertensive adolescent girls. Jumping rope is an easily accessible exercise modality that may have important health implications for CVD prevention in younger populations.

Taekwondo training reduces blood catecholamine levels and arterial stiffness in postmenopausal women with stage-2 hypertension: randomized clinical trial.

Objective: Menopause is associated with a progressive impairment of vascular function and muscular strength in women. Accordingly, the purpose of this study was to determine if Taekwondo training could improve blood catecholamine levels, arterial stiffness, blood pressure (BP) and skeletal muscle strength in postmenopausal women with stage-2 hypertension. Methods: 20 postmenopausal women (70 ± 4 years old) with stage-2 hypertension were randomly assigned to a 1) Taekwondo training (TT; n = 10) or 2) Control (CON; n = 10) group. Taekwondo training was performed for 60 minutes/day, 3 days/week for 12-weeks. Results: There were significant (P < 0.05) group by time interactions for resting epinephrine (EP) and norepinephrine (NE) levels, with EP decreasing in the TT group and NE increasing in the CON group. Additionally, brachial-ankle pulse wave velocity, resting heart rate, and BP were significantly decreased, while hand grip and leg strength were significantly increased in the TT group compared to CON group. Conclusion: These results suggest that Taekwondo training can be a novel and beneficial mode of exercise for improving cardiovascular function and muscular strength in this population. Abbreviations: TT: Taekwondo training group; CON: control group; EP: epinephrine; NE: norepinephrine; ANS: autonomic nervous system; SNS: sympathetic nervous system; baPWV: brachial-ankle pulse wave velocity.

Prolonged sitting and peripheral vascular function: potential mechanisms and methodological considerations.

Sitting time is associated with increased risks for subclinical atherosclerosis and cardiovascular disease development, and this is thought to be partially due to sitting-induced disturbances in macro- and microvascular function as well as molecular imbalances. Despite surmounting evidence supporting these claims, contributing mechanisms to these phenomena remain largely unknown. In this review, we discuss evidence for potential mechanisms of sitting-induced perturbations in peripheral hemodynamics and vascular function and how these potential mechanisms may be targeted using active and passive muscular contraction methods. Furthermore, we also highlight concerns regarding the experimental environment and population considerations for future studies. Optimizing prolonged sitting investigations may allow us to not only better understand the hypothesized sitting-induced transient proatherogenic environment but to also enhance methods and devise mechanistic targets to salvage sitting-induced attenuations in vascular function, which may ultimately play a role in averting atherosclerosis and cardiovascular disease development.

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.

Influence of Local Muscle Cooling on Mitochondrial-Related Gene Expression at Rest.

The purpose of this study was to determine the impact of localized cooling of the skeletal muscle during rest on mitochondrial related gene expression. Thermal wraps were applied to the vastus lateralis of each limb of 12 participants. One limb received a cold application (randomized) (COLD), while the other did not (RT). Wraps were removed at the 4 h time point and measurements of skin temperature, blood flow, and intramuscular temperature were taken prior to a muscle biopsy. RT-qPCR was used to measure expression of genes associated with mitochondrial development. Skin and muscle temperatures were lower in COLD than RT (p < 0.05). Femoral artery diameter was lower in COLD after 4 h (0.62 ± 0.05 cm, to 0.60 ± 0.05 cm, p = 0.018). Blood flow was not different in COLD compared to RT (259 ± 69 mL·min-1 vs. 275 ± 54 mL·min-1, p = 0.20). PGC-1α B and GABPA expression was higher in COLD relative to RT (1.57-fold, p = 0.037 and 1.34-fold, p = 0.006, respectively). There was no difference (p > 0.05) in the expression of PGC-1α, NT-PGC-1α, PGC-1α A, TFAM, ESRRα, NRF1, GABPA, VEGF, PINK1, PARK 2, or BNIP3-L. The impact of this small magnitude of difference in gene expression of PGC-1α B and GABPA without alterations in other genes are unknown. There appears to be only limited impact of local muscle cooling on the transcriptional response related to mitochondrial development.

No Mitochondrial Related Transcriptional Changes in Human Skeletal Muscle after Local Heat Application.

The purpose of the study is to determine the impact of local heating on skeletal muscle transcriptional response related to mitochondrial biogenesis and mitophagy. Twelve healthy subjects (height, 176.0 ± 11.9 cm; weight, 83.6 ± 18.3 kg; and body composition, 19.0 ± 7.7% body fat) rested in a semi-reclined position for 4 h with a heated thermal wrap (HOT) around one thigh and a wrap without temperature regulation (CON) around the other (randomized). Skin temperature, blood flow, intramuscular temperature, and a skeletal muscle biopsy from the vastus lateralis were obtained after the 4 h intervention. Skin temperature via infrared thermometer and thermal camera was higher after HOT (37.3 ± 0.7 and 36.7 ± 1.0 °C, respectively) than CON (34.8 ± 0.7, 35.2 ± 0.8 °C, respectively, p < 0.001). Intramuscular temperature was higher in HOT (36.3 ± 0.4 °C) than CON (35.2 ± 0.8 °C, p < 0.001). Femoral artery blood flow was higher in HOT (304.5 ± 12.5 mL‧min-1) than CON (272.3 ± 14.3 mL‧min-1, p = 0.003). Mean femoral shear rate was higher in HOT (455.8 ± 25.1 s-1) than CON (405.2 ± 15.8 s-1, p = 0.019). However, there were no differences in any of the investigated genes related to mitochondrial biogenesis (PGC-1α, NRF1, GAPBA, ERRα, TFAM, VEGF) or mitophagy (PINK-1, PARK-2, BNIP-3, BNIP-3L) in response to heat (p > 0.05). These data indicate that heat application alone does not impact the transcriptional response related to mitochondrial homeostasis, suggesting that other factors, in combination with skeletal muscle temperature, are involved with previous observations of altered exercise induced gene expression with heat.

Microvascular Dysfunction in Peripheral Artery Disease: Is Heat Therapy a Viable Treatment?

Peripheral artery disease (PAD) is characterized by the development of atherosclerotic plaques in the lower-body conduit arteries. PAD is commonly accompanied by microvascular disease, which may result in poor wound healing, plantar ulcer development, and subsequent limb amputation. Understanding the mechanisms underlying the development of plantar ulcers is a critical step in the development of adequate treatment options for patients with PAD. Skin is classified into two major components: glabrous and non-glabrous. These skin types have unique microcirculation characteristics, making it important to differentiate between the two when investigating mechanisms for plantar ulcer development in PAD. There is evidence for a microcirculation compensatory mechanism in PAD. This is evident by the maintenance of basal microcirculation perfusion and capillary filling pressure despite a reduced pressure differential beyond an occlusion in non-critical limb ischemia PAD. The major mechanism for this compensatory system seems to be progressive vasodilation of the arterial network below an occlusion. Recently, heat therapies have emerged as novel treatment options for attenuating the progression of PAD. Heat therapies are capable of stimulating the cardiovascular system, which may lead to beneficial adaptations that may ultimately reduce fatigue during walking in PAD. Early work in this area has shown that full-body heating is capable of generating an acute cardiovascular response, similar to exercise, which has been suggested as the most efficient treatment modality and may generate adaptations with chronic exposure. Heat therapies may emerge as a conservative treatment option capable of attenuating the progression of PAD and ultimately impeding the development of plantar ulcers.

Sympathoinhibition and Vasodilation Contribute to the Acute Hypotensive Response of the Superoxide Dismutase Mimic, MnTnBuOE-2-PyP5+, in Hypertensive Animals.

The pathogenesis of hypertension has been linked to excessive levels of reactive oxygen species (ROS), particularly superoxide (O2•-), in multiple tissues and organ systems. Overexpression of superoxide dismutase (SOD) to scavenge O2•- has been shown to decrease blood pressure in hypertensive animals. We have previously shown that MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic currently in clinical trials as a normal tissue protector for cancer patients undergoing radiation therapy, can scavenge O2•- and acutely decrease normotensive blood pressures. Herein, we hypothesized that BuOE decreases hypertensive blood pressures. Using angiotensin II (AngII)-hypertensive mice, we demonstrate that BuOE administered both intraperitoneally and intravenously (IV) acutely decreases elevated blood pressure. Further investigation using renal sympathetic nerve recordings in spontaneously hypertensive rats (SHRs) reveals that immediately following IV injection of BuOE, blood pressure and renal sympathetic nerve activity (RSNA) decrease. BuOE also induces dose-dependent vasodilation of femoral arteries from AngII-hypertensive mice, a response that is mediated, at least in part, by nitric oxide, as demonstrated by ex vivo video myography. We confirmed this vasodilation in vivo using doppler imaging of the superior mesenteric artery in AngII-hypertensive mice. Together, these data demonstrate that BuOE acutely decreases RSNA and induces vasodilation, which likely contribute to its ability to rapidly decrease hypertensive blood pressure.

Twelve weeks of resistance band exercise training improves age-associated hormonal decline, blood pressure, and body composition in postmenopausal women with stage 1 hypertension: a randomized clinical trial.

OBJECTIVE: Menopause is often accompanied by an age-associated hormonal decline, increased blood pressure (BP), and poor body composition, which may collectively increase risks for cardiovascular disease. It is important to combat the negative effects on age-associated hormonal decline, BP, and body composition by incorporating appropriate lifestyle interventions, such as exercise. We sought to examine the effects of a 12-week resistance band exercise training program on aging-related hormones including estradiol, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and dehydroepiandrosterone sulfate (DHEA-S), BP, and body composition in postmenopausal women with stage 1 hypertension. METHODS: Postmenopausal women with stage 1 hypertension (n = 20) were recruited and randomly assigned to a 12-week resistance band exercise training group (EX, n = 10) or control group (CON, n = 10). The EX group performed a total-body resistance band exercise training program. Levels of estradiol, GH, IGF-1, DHEA-S, as well as BP and body composition were assessed before and after 12 weeks. RESULTS: There were significant group by time interactions (P < 0.05) for estradiol, GH, IGF-1, DHEA-S, and lean body mass, which significantly increased (P < 0.05), and systolic BP, total body mass, body mass index, and body fat percentage, which significantly decreased (P < 0.05) after EX compared to no changes in CON. There were no significant differences (P > 0.05) in diastolic BP after 12 weeks. CONCLUSIONS: These results indicate that 12 weeks of resistance band exercise may be an effective, easily accessible, and cost-efficient intervention for improving age-associated hormonal decline, high BP, and poor body composition in postmenopausal women with stage 1 hypertension. : Video Summary: http://links.lww.com/MENO/A494.

The Impact of Aspirin Intake on Lactate Dehydrogenase, Arterial Stiffness, and Oxidative Stress During High-Intensity Exercise: A Pilot Study.

Aspirin is a common nonsteroidal anti-inflammatory drug used to reduce fever, pain, and inflammation. However, aspirin's anti-inflammatory properties may also prevent increased levels of blood lactate dehydrogenase, vascular arterial stiffness and oxidative stress induced by high-intensity exercise. The purpose of this study was to investigate the effects of 4 weeks of aspirin supplementation on lactate dehydrogenase activity, lactate, arterial stiffness, and antioxidant capacity during high-intensity exercise in Taekwondo athletes. Participants were randomly divided into two groups: aspirin supplementation (n = 10) and placebo-control (n = 10). Blood levels of lactate dehydrogenase (LDH) enzyme activity and lactate were assessed to examine muscle damage and carotid-to-radial pulse wave velocity and the augmentation index were measured to examine arterial stiffness. Blood levels of superoxide dismutase, malondialdehyde, and glutathione peroxidase were assessed to determine antioxidant capacity and levels of oxidative stress. There were significant group × time interactions for enzyme activity of LDH (Δ-60 ± 24.36 U/L) and carotid-to-radial pulse wave velocity (Δ-1.33 ± 0.54 m/s), which significantly decreased (p < 0.05) following aspirin supplementation compared to placebo-control. Superoxide dismutase (Δ359 ± 110 U/gHb) and glutathione peroxidase (Δ28.2 ± 10.1 U/gHb) significantly decreased while malondialdehyde (0Δ3.0 ± 0.1 mmol/mL) significantly increased (p < 0.05) in the placebo-control group compared to the supplementation group. However, there were no changes in lactate concentration levels or augmentation index. These results reveal that low-dose aspirin supplementation would be a useful supplementation therapy to prevent high-intensity exercise training-induced increases in oxidative damage, inflammation, skeletal muscle fatigue, and arterial stiffness in elite Taekwondo athletes.

Effects of heated water-based versus land-based exercise training on vascular function in individuals with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease that is associated with poor vascular function, walking impairment, and reduced quality of life. Land-based exercise therapy (LBET) is frequently recommended to improve walking and reduce symptoms. Recently, evidence has suggested that heated-water exercise therapy (HWET) is an effective intervention for PAD. However, the efficacy of LBET versus HWET in PAD patients had not been elucidated. Therefore, we sought to compare effects of LBET with HWET on cardiovascular function, exercise tolerance, physical function, and body composition in PAD patients. PAD patients (n = 53) were recruited and randomly assigned to a LBET group (n = 25) or HWET group (n = 28). The LBET group performed treadmill walking, whereas the HWET group performed walking in heated water for 12 wk. Leg (legPWV) and brachial-to-ankle arterial stiffness (baPWV), blood pressure (BP), ankle-brachial index (ABI), 6-min walking distance (6MWD), claudication onset time (COT), physical function, and body composition were assessed before and after 12 wk. There were significant group-by-time interactions (P < 0.05) for legPWV, BP, 6MWD, COT, body composition, and resting metabolic rate (RMR). Both groups significantly reduced (P < 0.05) legPWV, BP, and body fat percentage, and HWET measures were significantly lower than LBET measures. Both groups significantly increased 6MWD, COT, and RMR, and HWET group measures were significantly greater than LBET measures. A time effect was noted for baPWV reduction in both groups (P < 0.05). These results suggest that both LBET and HWET improve cardiovascular function, exercise tolerance, and body composition, and HWET showed considerably greater improvements compared with LBET in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that although land-based exercise therapy is effective for reducing arterial stiffness and blood pressure in patients with peripheral artery disease (PAD), heated-water exercise therapy demonstrates greater benefits on vascular function. The greater improvements in muscular strength, time to onset of claudication, and exercise tolerance after heated-water exercise therapy may have clinical implications for improving quality of life in patients with PAD. The heated-water exercise therapy intervention demonstrated relatively higher exercise training adherence (∼88%) compared with the land-based exercise intervention (∼81%).

Habitual Combined Exercise Protects against Age-Associated Decline in Vascular Function and Lipid Profiles in Elderly Postmenopausal Women.

Postmenopausal status is associated with increased risks for cardiovascular diseases (CVD). This study investigated differences in vascular function, lipids, body composition, and physical fitness in elderly postmenopausal women active in combined resistance and aerobic exercise (CRAE) training for 1 year versus a sedentary cohort of similar-in-age counterparts. Elderly postmenopausal women performing habitual CRAE training for 1 year (age ~75 year; CRAE, n = 57) and elderly sedentary postmenopausal women (age ~78 year; SED, n = 44) were recruited. Arterial stiffness (brachial-to-ankle pulse-wave velocity, baPWV), blood pressure, blood lipids, anthropometrics, 2-min walking distance, and muscular strength were assessed for both groups. There were significant differences for baPWV, systolic blood pressure, low-density lipoprotein, and body fat percentage, which were significantly lower (p < 0.05) in CRAE vs. SED, and both 2 min walking distance and muscular strength were significantly greater (p < 0.05) in CRAE vs. SED. These results indicate that elderly postmenopausal women participating in habitual CRAE training may have better protection against risks for CVD and have better physical fitness compared to SED counterparts.