near-infrared-spectroscopy-during-reactive-hyperemia-for-assessment

Near-Infrared Spectroscopy During Reactive Hyperemia for the Assessment of Lower Limb Vascular Function

Vascular diseases of the lower limb contribute substantially to the&#160;global burden of cardiovascular disease and comorbidities such as diabetes. ...

University of the Sunshine Coast

Impaired endothelial function is observed with aging and in those with low cardiorespiratory fitness (V̇o). Improvements in endothelial function with exercise training are somewhat dependent on the intensity of exercise. While the acute stimulus for this improvement is not completely understood, it may, in part, be due to the flow-mediated dilation (FMD) response to acute exercise. We examined the hypothesis that exercise intensity alters the brachial (systemic) FMD response in elderly men and is modulated by V̇o Forty-seven elderly men were stratified into lower (V̇o = 24.3 ± 2.9 ml·kg·min;  = 27) and higher fit groups (V̇o = 35.4 ± 5.5 ml·kg·min;  = 20) after a test of cycling peak power output (PPO). In randomized order, participants undertook moderate-intensity continuous exercise (MICE; 40% PPO) or high-intensity interval cycling exercise (HIIE; 70% PPO) or no-exercise control. Brachial FMD was assessed at rest and 10 and 60 min after exercise. FMD increased after MICE in both groups {increase of 0.86% [95% confidence interval (CI), 0.17-1.56],  = 0.01} and normalized after 60 min. In the lower fit group, FMD was reduced after HIIE [reduction of 0.85% (95% CI, 0.12-1.58),  = 0.02] and remained decreased at 60 min. In the higher fit group, FMD was unchanged immediately after HIIE and increased after 60 min [increase of 1.52% (95% CI, 0.41-2.62),  < 0.01, which was correlated with V̇o,  = 0.41;  < 0.01]. In the no-exercise control, FMD was reduced in both groups after 60 min ( = 0.05). Exercise intensity alters the acute FMD response in elderly men and V̇o modulates the FMD response following HIIE but not MICE. The sustained decrease in FMD in the lower fit group following HIIE may represent a signal for vascular adaptation or endothelial fatigue. This study is the first to show that moderate-intensity continuous cycling exercise increased flow-mediated dilation (FMD) transiently before normalization of FMD after 1 h, irrespective of cardiorespiratory fitness level in elderly men. Interestingly, we show increased FMD after high-intensity cycling exercise in higher fit men, with a sustained reduction in FMD in lower fit men. The prolonged reduction in FMD after high-intensity cycling exercise may be associated with future vascular adaptation but may also reflect a period of increased cardiovascular risk in lower fit elderly men.

Cardiorespiratory fitness modulates the acute flow-mediated dilation response following high-intensity but not moderate-intensity exercise in elderly men.

Endothelial dysfunction is observed in patients with abdominal aortic aneurysm (AAA), who have increased risk of cardiovascular events and mortality. This study aimed to assess the acute effects of moderate- and higher-intensity exercise on endothelial function, as assessed by flow-mediated dilation (FMD), in AAA patients (74 ± 6 yr old, n = 22) and healthy adults (72 ± 5 yr old, n = 22). Participants undertook three randomized visits, including moderate-intensity continuous exercise [40% peak power output (PPO)], higher-intensity interval exercise (70% PPO), and a no-exercise control. Brachial artery FMD was assessed at baseline and at 10 and 60 min after each condition. Baseline FMD was lower [by 1.10% (95% confidence interval: 0.72-.81), P = 0.044] in AAA patients than in healthy adults. There were no group differences in FMD responses after each condition ( P = 0.397). FMD did not change after no-exercise control but increased by 1.21% (95% confidence interval: 0.69-1.73, P < 0.001) 10 min after moderate-intensity continuous exercise in both groups and returned to baseline after 60 min. Conversely, FMD decreased by 0.93% (95% confidence interval: 0.41-1.44, P < 0.001) 10 min after higher-intensity interval exercise in both groups and remained decreased after 60 min. We found that the acute response of endothelial function to exercise is intensity-dependent and similar between AAA patients and healthy adults. Our findings provide evidence that regular exercise may improve vascular function in AAA patients, as it does in healthy adults. Improved FMD after moderate-intensity exercise may provide short-term benefit. Whether the decrease in FMD after higher-intensity exercise represents an additional risk and/or a greater stimulus for vascular adaptation remains to be elucidated. NEW & NOTEWORTHY Abdominal aortic aneurysm patients have vascular dysfunction. We observed a short-term increase in vascular function after moderate-intensity exercise. Conversely, higher-intensity exercise induced a prolonged reduction in vascular function, which may be associated with both short-term increases in cardiovascular risk and signaling for longer-term vascular adaptation in abdominal aortic aneurysm patients.

Effects of acute exercise on endothelial function in patients with abdominal aortic aneurysm.

Inflammation and extracellular matrix degeneration contribute to abdominal aortic aneurysm (AAA) development. We aimed to assess the effect of exercise intensity on circulating biomarkers of inflammation and extracellular matrix degeneration in patients with AAA and healthy older adults.

Acute Inflammatory Responses to Exercise in Patients with Abdominal Aortic Aneurysm.

Markers of chronic inflammation increase with aging, and are associated with cardiovascular disease prevalence and mortality. Increases in fitness with exercise training have been associated with lower circulating concentrations of cytokines known to have pro-inflammatory actions (such as interleukin-6 [IL-6]) and higher circulating concentrations of anti-inflammatory cytokines (interleukin-10 [IL-10]). However, the effect of cardiorespiratory fitness on acute cytokine responses to a single bout of exercise in healthy older individuals is unknown. We compared the response of plasma cytokines IL-6, tumor necrosis factor-alpha (TNF-α) and IL-10 to a bout of moderate-intensity continuous and higher-intensity interval exercise between older individuals with higher and lower levels of cardiorespiratory fitness. Sixteen lower-fit (O: 22.6±2.8 mL.kg.min) and fourteen higher-fit participants (O: 37.4±5.9 mL.kg.min) completed three 24 min experimental protocols in a randomized order: (1) moderate-intensity continuous exercise (40% of peak power output [PPO]); (2) higher-intensity interval exercise (12 × 1 min intervals at 70% PPO separated by 1 min periods at 10% PPO); or (3) non-exercise control. Plasma cytokines were measured at rest, immediately after, and during 90 min of recovery following exercise or control. Plasma IL-6 concentrations at baseline were greater in the higher-fit compared to the lower-fit group ( = 0.02), with no difference in plasma IL-10 or TNF-α concentrations at baseline between groups. Plasma IL-6 and IL-10 concentrations in both groups increased immediately after all protocols (IL-6:  = 0.02, IL-10:  < 0.01). However, there was no difference in the IL-6 and IL-10 response between the exercise and non-exercise (control) protocols. After all protocols, no changes in plasma TNF-α concentrations were observed in either the higher- or lower-fit groups. In this study, basal concentrations of circulating IL-6 were elevated in older individuals with higher levels of cardiorespiratory fitness. However, changes in plasma cytokine concentrations after exercise were not different to changes after non-exercise control in both the lower- and higher-fit groups.

Cytokine Responses to Acute Exercise in Healthy Older Adults: The Effect of Cardiorespiratory Fitness.

Increased arterial stiffness is observed with ageing and in individuals with low cardiorespiratory fitness ([Formula: see text]O), and associated with cardiovascular risk. Following an exercise bout, transient arterial stiffness reductions offer short-term benefit, but may depend on exercise intensity. This study assessed the effects of exercise intensity on post-exercise arterial stiffness in older adults with varying fitness levels.

Effects of exercise intensity and cardiorespiratory fitness on the acute response of arterial stiffness to exercise in older adults.

Short-term changes in arterial stiffness with exercise are proposed to better reflect vascular impairments than resting measures alone and are suggested as a prognostic indicator of cardiovascular risk in older adults. Arterial stiffness indices are reliable at rest, but the time-course and reliability of postexercise changes in arterial stiffness in older adults are unknown. The precision of postexercise changes in arterial stiffness should be determined prior to their use in large prospective trials. This study assessed the between-day reliability of the changes in pulse wave velocity (PWV), augmentation index (AIx75) and reflection magnitude (RM) following an exercise bout in older adults. Ten older adults (71 ± 5 years) were tested on three separate days, 7 days apart. PWV, AIx75 and RM were assessed at rest, immediately post and at 20, 40 and 60 min during recovery after moderate-intensity cycling. Intraclass correlation coefficient (ICC) and reliability coefficient (RC) were used to assess the relative and absolute reliability of arterial stiffness responses. PWV increased, and RM decreased immediately after exercise (P<0·05), and returned to baseline during recovery. AIx decreased during recovery (P<0·001). Resting ICC values were 0·91 (PWV), 0·72 (AIx75) and 0·40 (RM). Reliability of the immediate changes following exercise was high for PWV (ICC:0·87, RC:1·9 m s ) and moderate for AIx75 (ICC:0·64, RC:7%) and RM (ICC:0·59, RC:9%). Reliability of the postexercise responses was similar to that at rest for all measures of arterial stiffness. These findings indicate that postexercise changes in arterial stiffness indices are reliable in healthy older adults and supports further investigation of the prognostic value of these responses.

Reliability of arterial stiffness indices at rest and following a single bout of moderate-intensity exercise in older adults.

Abdominal aortic aneurysm (AAA) is an important cause of death in older adults, which has no current drug therapy. Inflammation and abnormal redox status are believed to be key pathogenic mechanisms for AAA. In light of evidence correlating inflammation with aberrant fatty acid profiles, this study compared erythrocyte fatty acid content in 43 AAA patients (diameter 3.0-4.5 cm) and 52 healthy controls. In addition, the effect of omega-3 PUFA (n-3 PUFA) supplementation on erythrocyte fatty acid content was examined in a cohort of 30 AAA patients as part of a 12 week randomized placebo-controlled clinical trial. Blood analyses identified associations between AAA and decreased linoleic acid (LA), and AAA and increased Δ6-desaturase activity and biosynthesis of arachidonic acid (AA) from LA. Omega-3 PUFA supplementation (1.5 g DHA + 0.3 g EPA/day) decreased red blood cell distribution width (14.8 ± 0.4% to 13.8 ± 0.2%;  = 0.003) and levels of pro-inflammatory n-6 PUFAs (AA, 12.46 ± 0.23% to 10.14 ± 0.3%,  < 0.001; adrenic acid, 2.12 ± 0.13% to 1.23 ± 0.09%;  < 0.001). In addition, Δ-4 desaturase activity increased (DHA/docosapentaenoic acid ratio, 1.85 ± 0.14 to 3.93 ± 0.17;  < 0.001) and elongase 2/5 activity decreased (adrenic acid/AA ratio, 0.17 ± 0.01 to 0.12 ± 0.01;  < 0.01) following supplementation. The findings suggest that n-3 PUFAs improve fatty acid profiles and ameliorate factors associated with inflammation in AAA patients.

n-3 PUFAs improve erythrocyte fatty acid profile in patients with small AAA: a randomized controlled trial.

Innate immune cell defects contribute to severe autoimmunity and the pathogenesis of inflammatory disease. Monocyte-derived macrophages typically retain disease related signatures and represent an excellent in vitro model to uncover and validate mechanisms contributing to specific pathological states. Monocyte isolation procedures vary widely in terms of purity, yield, cost, degree of technical difficulty and volume of peripheral blood needed. This paper outlines a novel isolation method that yields monocytes through density gradient centrifugation (Ficoll® and hyperosmotic Percoll®). The protocol has been optimised for small volumes of blood (42 ml) and is simple, reproducible and inexpensive compared to other methods. Monocyte recovery is 70% (relative to monocyte numbers within the buffy coat) and the highly functional macrophages produced are characterised by excellent purity (98.6 ± 0.6%) and intact activation and phagocytic capacities. The method is well suited to investigations involving patient populations where a particular subset of immune cells is known to contribute to the pathogenesis of a specific disease or is aberrant as a consequence of that disease.

A simple and effective method for the isolation and culture of human monocytes from small volumes of peripheral blood.

Abdominal aortic aneurysm (AAA) is associated with inflammation and oxidative stress, the latter of which contributes to activation of macrophages, a prominent cell type in AAA. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to limit oxidative stress in animal models of AAA. The aim of this study was to evaluate the effect of the n-3 PUFA docosahexaenoic acid (DHA) on antioxidant defence in macrophages from patients with AAA. Cells were obtained from men with small AAA (diameter 3.0-4.5 cm, 75 ± 6 yr, n = 19) and age- matched male controls (72 ± 5 yr, n = 41) and incubated with DHA for 1 h before exposure to 0.1 µg/mL lipopolysaccharide (LPS) for 24 h. DHA supplementation decreased the concentration of tumour necrosis factor-α (TNF-α; control, 42.1 ± 13.6 to 5.1 ± 2.1 pg/ml, p < 0.01; AAA, 25.2 ± 9.8 to 1.9 ± 0.9 pg/ml, p < 0.01) and interleukin-6 (IL-6; control, 44.9 ± 7.7 to 5.9 ± 2.0 pg/ml, p < 0.001; AAA, 24.3 ± 5.2 to 0.5 ± 0.3 pg/ml, p < 0.001) in macrophage supernatants. DHA increased glutathione peroxidase activity (control, 3.2 ± 0.3 to 4.1 ± 0.2 nmol/min/ml/μg protein, p = 0.004; AAA, 2.3 ± 0.5 to 3.4 ± 0.5 nmol/min/ml/μg protein, p = 0.008) and heme oxygenase-1 mRNA expression (control, 1.5-fold increase, p < 0.001). The improvements in macrophage oxidative stress status serve as a stimulus for further investigation of DHA in patients with AAA.

Omega-3 fatty acids decrease oxidative stress and inflammation in macrophages from patients with small abdominal aortic aneurysm.

Elevated arterial stiffness is a characteristic of abdominal aortic aneurysm (AAA), and is associated with AAA growth and cardiovascular mortality. A bout of exercise transiently reduces aortic and systemic arterial stiffness in healthy adults. Whether the same response occurs in patients with AAA is unknown. The effect of moderate- and higher intensity exercise on arterial stiffness was assessed in patients with AAA and healthy adults.

Aortic and Systemic Arterial Stiffness Responses to Acute Exercise in Patients With Small Abdominal Aortic Aneurysms.

Macrophages are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). This study examined the environmentally conditioned responses of AAA macrophages to inflammatory stimuli. Plasma- and blood-derived monocytes were separated from the whole blood of patients with AAA (30-45 mm diameter;  = 33) and sex-matched control participants ( = 44). Increased concentrations of pro-inflammatory and pro-oxidant biomarkers were detected in the plasma of AAA patients, consistent with systemic inflammation and oxidative stress. However, in monocyte-derived macrophages, a suppressed cytokine response was observed in AAA compared to the control following stimulation with lipopolysaccharide (LPS) (tumor necrosis factor alpha (TNF-α) 26.9 ± 3.3 vs. 15.5 ± 3.2 ng/mL,  < 0.05; IL-6 3.2 ± 0.6 vs. 1.4 ± 0.3 ng/mL,  < 0.01). LPS-stimulated production of 8-isoprostane, a biomarker of oxidative stress, was also markedly lower in AAA compared to control participants. These findings are consistent with developed tolerance in human AAA macrophages. As Toll-like receptor 4 (TLR4) has been implicated in tolerance, macrophages were examined for changes in TLR4 expression and distribution. Although TLR4 mRNA and protein expression were unaltered in AAA, cytosolic internalization of receptors and lipid rafts was found. These findings suggest the inflamed, pro-oxidant AAA microenvironment favors macrophages with an endotoxin-tolerant-like phenotype characterized by a diminished capacity to produce pro-inflammatory mediators that enhance the immune response.

Endotoxin Tolerance in Abdominal Aortic Aneurysm Macrophages, In Vitro: A Case-Control Study.

Glycine receptors (GlyRs) containing the α2 subunit govern cell fate, neuronal migration and synaptogenesis in the developing cortex and spinal cord. Rare missense variants and microdeletions in the X-linked GlyR α2 subunit gene () have been associated with human autism spectrum disorder (ASD), where they typically cause a  via protein truncation, reduced cell-surface trafficking and/or reduced glycine sensitivity (e.g., Δex8-9 and extracellular domain variants p.N109S and p.R126Q). However, the GlyR α2 missense variant p.R323L in the intracellular M3-M4 domain results in a  characterized by slower synaptic decay times, longer duration active periods and increases in channel conductance. This study reports the functional characterization of four missense variants in  associated with ASD or developmental disorders (p.V-22L, p.N38K, p.K213E, p.T269M) using a combination of bioinformatics, molecular dynamics simulations, cellular models of GlyR trafficking and electrophysiology in artificial synapses. The GlyR α2 variant resulted in altered predicted signal peptide cleavage and a reduction in cell-surface expression, suggestive of a . Similarly, GlyR α2 homomers showed reduced cell-surface expression, a reduced affinity for glycine and a reduced magnitude of IPSCs in artificial synapses. By contrast, GlyR α2 homomers showed a slight reduction in cell-surface expression, but IPSCs were larger, with faster rise/decay times, suggesting a . Lastly, GlyR α2 homomers exhibited a high glycine sensitivity accompanied by a substantial leak current, suggestive of an  that could dramatically enhance glycinergic signaling. These results may explain the heterogeneity of clinical phenotypes associated with  mutations and reveal that missense variants can result in a loss, gain or alteration of GlyR α2 function. In turn, these GlyR α2 missense variants are likely to either negatively or positively deregulate cortical progenitor homeostasis and neuronal migration in the developing brain, leading to changes in cognition, learning, and memory.

Article	Year
Cardiorespiratory fitness modulates the acute flow-mediated dilation response following high-intensity but not moderate-intensity exercise in elderly men. Journal of applied physiology (Bethesda, Md. : 1985)\| PubMed ID: 28209742	2017
Effects of acute exercise on endothelial function in patients with abdominal aortic aneurysm. American journal of physiology. Heart and circulatory physiology\| PubMed ID: 28939648	2018
Acute Inflammatory Responses to Exercise in Patients with Abdominal Aortic Aneurysm. Medicine and science in sports and exercise\| PubMed ID: 29210916	2018
Cytokine Responses to Acute Exercise in Healthy Older Adults: The Effect of Cardiorespiratory Fitness. Frontiers in physiology\| PubMed ID: 29599722	2018
Effects of exercise intensity and cardiorespiratory fitness on the acute response of arterial stiffness to exercise in older adults. European journal of applied physiology\| PubMed ID: 29850932	2018
Reliability of arterial stiffness indices at rest and following a single bout of moderate-intensity exercise in older adults. Clinical physiology and functional imaging\| PubMed ID: 29956874	2019
n-3 PUFAs improve erythrocyte fatty acid profile in patients with small AAA: a randomized controlled trial. Journal of lipid research\| PubMed ID: 30914500	2019
A simple and effective method for the isolation and culture of human monocytes from small volumes of peripheral blood. Journal of immunological methods\| PubMed ID: 31229469	2019
Omega-3 fatty acids decrease oxidative stress and inflammation in macrophages from patients with small abdominal aortic aneurysm. Scientific reports\| PubMed ID: 31506475	2019
Aortic and Systemic Arterial Stiffness Responses to Acute Exercise in Patients With Small Abdominal Aortic Aneurysms. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery\| PubMed ID: 31631005	2019
Endotoxin Tolerance in Abdominal Aortic Aneurysm Macrophages, In Vitro: A Case-Control Study. Antioxidants (Basel, Switzerland)\| PubMed ID: 32967278	2020
Loss, Gain and Altered Function of GlyR α2 Subunit Mutations in Neurodevelopmental Disorders. Frontiers in molecular neuroscience\| PubMed ID: 35571374	2022

Mark Windsor

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