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What is the central question of this study? We sought to investigate whether peripheral and cerebrovascular function are impaired in early and late postmenopausal females compared with premenopausal females, while also accounting for nitric oxide and estradiol levels. What is the main finding and its importance? We observed no differences in peripheral vascular and cerebrovascular function between healthy and physically active premenopausal females and early and late postmenopausal females. Our findings contradict previous cross-sectional observations of vascular and cerebrovascular dysfunction across menopause. Longitudinal studies assessing vascular and cerebrovascular outcomes across the menopausal transition are warranted.The risk of cardiovascular and cerebrovascular disease increases in ageing females, coinciding with the onset of menopause. Differences in peripheral and cerebrovascular function across menopausal stages, however, are poorly characterized. The aim of this study was to compare peripheral and cerebrovascular function between healthy premenopausal (PRE), early (1-6 years after final menstrual period; E-POST) and late (6 years after final menstrual period; L-POST) postmenopausal females. We also explored the association between reproductive hormones, NO bioavailability and cerebrovascular function. In 39 females (40-65 years of age), we measured arterial stiffness, brachial artery flow-mediated dilatation, and cerebrovascular reactivity (CVR) to hypercapnia in the middle (MCAv) and internal (ICA) carotid arteries. Follicle-stimulating hormone, estradiol, progesterone and plasma nitrate and nitrite concentrations were also measured. Years since final menstrual period (PRE, 0 ± 0 years; E-POST, 3 ± 1 years; L-POST, 11 ± 4 years; P 0.001) and estradiol levels (PRE, 145.5 ± 65.6 pg ml

Purpose Our aim was to compare cerebrovascular and systemic vascular function between older adults with and without mild cognitive impairment (MCI), and to determine which measures of vascular function best predict the presence of MCI. Methods In 41 adults with MCI and 33 adults without MCI (control) we compared middle cerebral artery velocity (MCAv) and cerebrovascular pulsatility index (PI) at rest, cerebrovascular reactivity to CO2, and responsiveness to changes in blood pressure (%∆MCAv/%∆MAP). Systemic vascular function was assessed by flow-mediated dilation (FMD) and stiffness by pulse wave velocity (PWV). Results Cerebrovascular PI was higher in MCI compared with control (mean ± SD: 1.17 ± 0.27 vs. 1.04 ± 0.21), and MCI exhibited a lower %∆MCAv/%∆MAP (1.26 ± 0.44 vs. 1.50 ± 0.55%). Absolute (p = 0.76) and relative cerebrovascular reactivity to CO2 (p = 0.34) was similar between MCI and control. When age was included as a covariate the significant difference in cerebral PI between groups was lost. PWV was higher (13.2 ± 2.2 vs. 11.3 ± 2.5 m s−1) and FMD% (4.41 ± 1.70 vs. 5.43 ± 2.15%) was lower in MCI compared with control. FMD% was positively associated with PI across the cohort. Logistic regression analysis indicated that FMD and PWV significantly discriminated between MCI and controls, independent of age, whereas the inclusion of cerebrovascular measures did not improve the predictive accuracy of the model. Conclusion These findings raise the possibility that early changes in systemic vascular stiffness and endothelial function may contribute to altered cerebrovascular haemodynamics and impaired cognitive function, and present potential targets for prevention and treatment strategies in people with MCI.

Prior studies into road safety have concentrated largely on studying unsafe forms of driving behaviour such as aggressive, stressed, and risky driving. Little attention has been given to ‘positive’ driving behaviour, such as how pro-social driving may help to promote cooperation with other road users and decrease incidences of aggressive and stressful driving. This study aimed to compare the impact of courteous and discourteous driving on the immediate physical health of other drivers (blood pressure, heart rate, and markers of stress) whilst controlling for other recognized factors responsible for driver stress such as road infrastructure (e.g. roadworks, traffic lights, freeways) and driving maneuvers (e.g. merging, tail-gaiting, navigating roundabouts). Using actors in a deception study, a naturalistic driving scenario was created in a lab-based simulation. All participants (n = 10; 39 ± 14.5 years) drove the same route in a simulator and engaged with the same driving behaviours and other virtual road users on two separate occasions separated by 7 days. The difference between conditions was whether the participant interacted with other drivers who displayed: a) courteous or b) discourteous behaviours. Blood pressure, heart rate variability and salivary hormone concentrations (cortisol and alpha amylase) were measured before and immediately after each simulated drive. After interacting with the discourteous drivers, participants experienced significantly higher mean arterial blood pressure, systolic and diastolic pressure, central systolic and diastolic pressure, and heart rate, and lower heart rate variability (indicative of acute stress) compared to interacting with the courteous drivers. Conversely, these markers of stress were reduced after interacting with the courteous drivers. The results support courtesy on the road to provide short-term benefits for the recipient of the action, while also increasing road safety more generally.

Background: While the efficacy of sprint interval training (SIT) to provide positive health effects in inactive populations is established, feasibility is associated with enjoyment and safety, which are dependent on the acute physiological and perceptual responses. The recovery format likely influences physiological and perceptual responses that occur during and immediately after SIT. It was hypothesized that during SIT interspersed with active recovery periods, enjoyment and blood pressure (BP) values would be higher compared with passive recovery periods, in inactive participants. Methods: Twelve males (mean ± SD; age 23 ± 3 y) completed 3 exercise sessions on a cycle ergometer in a randomized order on separate days: (a) SIT with passive recovery periods between 4 bouts (SITPASS), (b) SIT with active recovery periods between 4 bouts (SITACT), and (c) SITACT with the 4 SIT bouts replaced with passive periods. BP was measured immediately after each bout and every 2 min during a 6 min recovery. Physical activity enjoyment was measured during postexercise recovery. Results: There were no significant differences in physical activity enjoyment or systolic BP between SITPASS and SITACT. Diastolic BP was lower during recovery in SITACT (P = 0.025) and SITPASS (P = 0.027), compared with resting BP. Furthermore, diastolic BP was lower after 6 min of recovery following SITPASS, compared with SITACT (P = 0.01). Conclusion: Exercise enjoyment and acute systolic BP responses were independent of SIT recovery format in inactive men. Reductions in diastolic BP were greater and more prolonged after SIT protocols that included passive recovery periods.

Objectives To assess physical activity (PA), mental health and well-being of adults in the United Kingdom (UK), Ireland, New Zealand and Australia during the initial stages of National governments’ Coronavirus disease (COVID-19) containment responses. Design Observational, cross-sectional. Methods An online survey was disseminated to adults (n = 8,425; 44.5 ± 14.8y) residing in the UK, Ireland, New Zealand and Australia within the first 2-6 weeks of government-mandated COVID-19 restrictions. Main outcome measures included: Stages of Change scale for exercise behaviour change; International Physical Activity Questionnaire (short-form); World Health Organisation-5 Well-being Index; and the Depression Anxiety and Stress Scale-9. Results Participants who reported a negative change in exercise behaviour from before initial COVID-19 restrictions to during the initial COVID-19 restrictions demonstrated poorer mental health and well-being compared to those demonstrating either a positive-or no change in their exercise behaviour (p < 0.001). Whilst women reported more positive changes in exercise behaviour, young people (18-29y) reported more negative changes (both p < 0.001). Individuals who had more positive exercise behaviours reported better mental health and well-being (p < 0.001). Although there were no differences in PA between countries, individuals in New Zealand reported better mental health and well-being (p < 0.001). Conclusion The initial COVID-19 restrictions have differentially impacted upon PA habits of individuals based upon their age and sex, and therefore have important implications for international policy and guideline recommendations. Public health interventions that encourage PA should target specific groups (e.g., men, young adults) who are most vulnerable to the negative effects of physical distancing and/or self-isolation.

IntroductionRegular aerobic exercise is associated with improved cognitive function, implicating it as a strategy to reduce dementia risk. This is reinforced by the association between greater cardiorespiratory fitness and larger brain volume, superior cognitive performance and lower dementia risk. However, the optimal aerobic exercise dose, namely the intensity and mode of delivery, to improve brain health and lower dementia risk has received less attention. We aim to determine the effect of different doses of aerobic exercise training on markers of brain health in sedentary middle-aged adults, hypothesising that high-intensity interval training (HIIT) will be more beneficial than moderate-intensity continuous training (MICT).Methods and analysisIn this two-group parallel, open-label blinded endpoint randomised trial, 70 sedentary middle-aged (45–65 years) adults will be randomly allocated to one of two 12-week aerobic exercise training interventions matched for total exercise training volume: (1) MICT (n=35) or HIIT (n=35). Participants will perform ~50 min exercise training sessions, 3 days per week, for 12 weeks. The primary outcome will be measured as between-group difference in cardiorespiratory fitness (peak oxygen uptake) change from baseline to the end of training. Secondary outcomes include between-group differences in cognitive function and ultra-high field MRI (7T) measured markers of brain health (brain blood flow, cerebrovascular function, brain volume, white matter microstructural integrity and resting state functional brain activity) changes from baseline to the end of training.Ethics and disseminationThe Victoria University Human Research Ethics Committee (VUHREC) has approved this study (HRE20178), and all protocol modifications will be communicated to the relevant parties (eg, VUHREC, trial registry). Findings from this study will be disseminated via peer-review publications, conference presentations, clinical communications and both mainstream and social media.Trial registration numberANZCTR12621000144819.

The COVID-19 pandemic markedly changed how healthcare services are delivered and telehealth delivery has increased worldwide. Whether changes in healthcare delivery borne from the COVID-19 pandemic impact effectiveness is unknown. Therefore, we examined the effectiveness of exercise physiology services provided during the COVID-19 pandemic.This prospective cohort study included 138 clients who received exercise physiology services during the initial COVID-19 pandemic. Outcome measures of interest were EQ-5D-5L, EQ-VAS, patient-specific functional scale, numeric pain rating scale and goal attainment scaling.Most (59%, n = 82) clients received in-person delivery only, whereas 8% (n = 11) received telehealth delivery only and 33% (n = 45) received a combination of delivery modes. Mean (SD) treatment duration was 11 (7) weeks and included 12 (6) sessions lasting 48 (9) minutes. The majority (73%, n = 101) of clients completed 80% of exercise sessions. Exercise physiology improved mobility by 14% (β = 0.23, P = 0.003), capacity to complete usual activities by 18% (β = 0.29, P 0.001), capacity to complete important activities that the client was unable to do or having difficulty performing by 54% (β = 2.46, P 0.001), current pain intensity by 16% (β = - 0.55, P = 0.038) and goal attainment scaling t-scores by 50% (β = 18.37, P 0.001). Effectiveness did not differ between delivery modes (all: P 0.087).Exercise physiology services provided during the COVID-19 pandemic improved a range of client-reported outcomes regardless of delivery mode. Further exploration of cost-effectiveness is warranted.

Physical activity (PA) participation was substantially reduced at the start of the COVID-19 pandemic. The purpose of this study was to assess the association between PA, mental health, and wellbeing during and following the easing of COVID-19 restrictions in the United Kingdom (UK) and New Zealand (NZ). In this study, 3363 adults completed online surveys within 2–6 weeks of initial COVID-19 restrictions (April/May 2020) and once restrictions to human movement had been eased. Outcome measures included the International Physical Activity Questionnaire Short-Form, Depression Anxiety and Stress Scale-9 (mental health) and World Health Organisation-5 Wellbeing Index. There were no differences in PA, mental health or wellbeing between timepoints (p > 0.05). Individuals engaging in moderate or high volume of PA had significantly better mental health (−1.1 and −1.7 units, respectively) and wellbeing (11.4 and 18.6 units, respectively) than individuals who engaged in low PA (p < 0.001). Mental health was better once COVID-19 restrictions were eased (p < 0.001). NZ had better mental health and wellbeing than the UK (p < 0.001). Participation in moderate-to-high volumes of PA was associated with better mental health and wellbeing, both during and following periods of COVID-19 containment, compared to participation in low volumes of PA. Where applicable, during the current or future pandemic(s), moderate-to-high volumes of PA should be encouraged.

Community-based exercise programs for older adults play a potentially important role in mitigating the decline in functional outcomes, body composition, psychosocial outcomes, and cardiovascular health outcomes that commonly occurs with advancing age. There is a limited understanding of the characteristics and effectiveness of community-based exercise programs, particularly when those programs are offered outside metropolitan areas. Rural/regional settings face unique challenges, such as limited access to equipment/resources, transportation, and services, as well as significant costs to run programs. The objective of this scoping review was to characterise studies in the field that have aimed to implement community-based programs in settings identified as rural / regional. A secondary aim was to establish guidance for future exercise programs in this setting and highlight future research directions. A total of 12 studies were conducted in settings identified as rural/regional areas in various countries across the world were included. Of the included studies, five were randomised controlled trials. The majority of included studies reported on functional outcomes (83%) and psychosocial outcomes (75%), yet only 42% reported body composition, 17% reported cardiovascular health and 17% reported dietary outcomes. Low male representation was observed, with women outnumbering men in 7 of 12 studies. There was also minimal investigation of qualitative outcomes in existing community-based exercise programs in rural/regional settings, presenting a key gap for future research to address. Study Protocol: https://osf.io/txpm3/ . Date of registration: 20 July 2020.

Evidence suggests that cerebrovascular hemodynamic disturbances underlie cognitive deterioration secondary to cardiovascular disease (CVD), including manifestations other than stroke, but the mechanisms remain unclear. To date, the majority of studies have used neuropsychological measures validated for the detection of clinically significant cognitive decline but lack the sensitivity to accurately detect subclinical or subtle cognitive changes. The N2 and P3 components of the event-related potential are sensitive markers of attention and cognitive processing, and are valuable in the assessment of age-related cognitive changes and neurodegenerative disease. The aims of this study were to test (a) the sensitivity of N2 and P3 components in differentiating older adults with CVD from healthy controls, and (b) whether cerebrovascular hemodynamics are associated with alterations in attention in persons with non-stroke CVD. Older adults with CVD (n = 20) and healthy older adults (n = 20) without cognitive impairment or history of stroke and matched for age, were recruited. Cerebral blood flow velocity of the middle cerebral artery (MCAv) and Gosling’s Pulsatility Index (PI) were assessed using Transcranial Doppler ultrasound (TCD). ERPs were elicited using a two-tone auditory oddball task. N2 amplitude was significantly reduced in the CVD group at midline frontal, central and parietal sites (p 0.6). No significant group differences were observed in N2 latency, P3 amplitude, or P3 latency. Further, MCAv and PI were strongly associated with N2 amplitude in the CVD group, such that greater MCAv was associated with reductions in N2 amplitude (b = −0.58, p = .018), whilst PI was associated with increases in N2 amplitude (b = 0.66, p = .006). No relationships between MCAv or PI with N2 or P3 ERP components were observed in the healthy control group. The data reported here suggest that a reduction in N2 amplitude may be an important objective indicator of subclinical cognitive and attentional alterations in non-stroke CVD, and support the notion that cerebrovascular hemodynamic disturbances play a role in the pathogenesis of cognitive deterioration secondary to non-stroke CVD.

Objective/background: 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. Methods: Twenty-two men with small diameter AAAs (36 ± 5 mm; mean age 74 ± 6 years) and 22 healthy adults (mean age 72 ± 5 years) were included. Aortic stiffness was measured using carotid to femoral pulse wave velocity (PWV), and systemic arterial stiffness was estimated from the wave reflection magnitude (RM) and augmentation index (Alx75). Measurements were performed at rest and during 90 min of recovery following three separate test sessions in a randomised order: (i) moderate intensity continuous exercise; (ii) higher intensity interval exercise; or (iii) seated rest. Results: At rest, PWV was higher in patients with AAA than in healthy adults (p < .001), while AIx75 and RM were similar between groups. No differences were observed between AAA patients and healthy adults in post-exercise aortic and systemic arterial stiffness after either exercise protocol. When assessed as the change from baseline (delta, Δ), post-exercise ΔAIx75 was not different to the seated rest protocol. Conversely, post-exercise ΔPWV and ΔRM were both lower at all time points than seated rest (p < .001). ΔPWV was lower immediately after higher intensity than after moderate intensity exercise (p = .015). Conclusion: High resting aortic stiffness in patients with AAA is not exacerbated after exercise. There was a similar post-exercise attenuation in arterial stiffness between patients with AAA and healthy adults compared with seated rest. This effect was most pronounced following higher intensity interval exercise, suggesting that this form of exercise may be a safe and effective adjunctive therapy for patients with small AAAs.

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%; P = 0.003) and levels of pro-inflammatory n-6 PUFAs (AA, 12.46 ± 0.23% to 10.14 ± 0.3%, P < 0.001; adrenic acid, 2.12 ± 0.13% to 1.23 ± 0.09%; P < 0.001). In addition, Δ-4 desaturase activity increased (DHA/docosapentaenoic acid ratio, 1.85 ± 0.14 to 3.93 ± 0.17; P < 0.001) and elongase 2/5 activity decreased (adrenic acid/AA ratio, 0.17 ± 0.01 to 0.12 ± 0.01; P < 0.01) following supplementation. The findings suggest that n-3 PUFAs improve fatty acid profiles and ameliorate factors associated with inflammation in AAA patients.

Purpose: Leg muscle microvascular blood flow (perfusion) is impaired in response to maximal exercise in patients with peripheral artery disease (PAD); however, during submaximal exercise, microvascular perfusion is maintained due to a greater increase in microvascular blood volume compared with that seen in healthy adults. It is unclear whether this submaximal exercise response reflects a microvascular impairment, or whether it is a compensatory response for the limited conduit artery flow in PAD. Therefore, to clarify the role of conduit artery blood flow, we compared whole-limb blood flow and skeletal muscle microvascular perfusion responses with exercise in patients with PAD (n=9; 60±7 years) prior to, and following, lower-limb endovascular revascularization. Materials and Methods: Microvascular perfusion (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after a 5 minute bout of submaximal intermittent isometric plantar-flexion exercise using contrast-enhanced ultrasound imaging. Exercise contraction-by-contraction whole-leg blood flow and vascular conductance were measured using strain-gauge plethysmography. Results: With revascularization there was a significant increase in whole-leg blood flow and conductance during exercise (p−1; p=0.38). However, the parameters that determine microvascular perfusion changed, with a reduction in the microvascular volume response to exercise (pre-revascularization: 6.76±3.56; post-revascularization: 2.42±0.69 aU; p−1; p=0.02). Conclusion: These findings suggest that patients with PAD compensate for the conduit artery blood flow impairment with an increase in microvascular blood volume to maintain muscle perfusion during submaximal exercise. Clinical Impact The findings from this study support the notion that the impairment in conduit artery blood flow in patients with PAD leads to compensatory changes in microvascular blood volume and flow velocity to maintain muscle microvascular perfusion during submaximal leg exercise. Moreover, this study demonstrates that these microvascular changes are reversed and become normalized with successful lower-limb endovascular revascularization.

We address two aims: Aim 1 (Fitness Review) compares the effect of higher cardiorespiratory fitness (CRF) (e.g., endurance athletes) with lower CRF (e.g., sedentary adults) on cerebrovascular outcomes, including middle cerebral artery velocity (MCAv), cerebrovascular reactivity and resistance, and global cerebral blood flow, as assessed by transcranial Doppler (TCD) or magnetic resonance imaging (MRI). Aim 2 (Exercise Training Review) determines the effect of exercise training on cerebrovascular outcomes. Systematic review of studies with meta-analyses where appropriate. Certainty of evidence was assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Twenty studies (18 using TCD) met the eligibility criteria for Aim 1, and 14 studies (8 by TCD) were included for Aim 2. There was a significant effect of higher CRF compared with lower CRF on cerebrovascular resistance (effect size = -0.54, 95% confidence interval = -0.91 to -0.16) and cerebrovascular reactivity (0.98, 0.41-1.55). Studies including males only demonstrated a greater effect of higher CRF on cerebrovascular resistance than mixed or female studies (male only: -0.69, -1.06 to -0.32; mixed and female studies: 0.10, -0.28 to 0.49). Exercise training did not increase MCAv (0.05, -0.21 to 0.31) but showed a small nonsignificant improvement in cerebrovascular reactivity (0.60, -0.08 to 1.28; P = 0.09). Exercise training showed heterogeneous effects on regional but little effect on global cerebral blood flow as measured by MRI. High CRF positively effects cerebrovascular function, including decreased cerebrovascular resistance and increased cerebrovascular reactivity; however, global cerebral blood flow and MCAv are primarily unchanged following an exercise intervention in healthy and clinical populations.NEW & NOTEWORTHY Higher cardiorespiratory fitness is associated with lower cerebrovascular resistance and elevated cerebrovascular reactivity at rest. Only adults with a true-high fitness based on normative data exhibited elevated middle cerebral artery velocity. The positive effect of higher compared with lower cardiorespiratory fitness on resting cerebrovascular resistance was more evident in male-only studies when compared with mixed or female-only studies. A period of exercise training resulted in negligible changes in middle cerebral artery velocity and global cerebral blood flow, with potential for improvements in cerebrovascular reactivity.

Endothelial function, assessed using brachial artery flow-mediated dilation (FMD), predicts future cardiovascular disease (CVD) risk. This study established age- and sex-specific reference intervals for brachial artery FMD in healthy individuals and examined the relation with CVD risk factors. In a retrospective study design, we pooled brachial artery FMD (acquired according to expert-consensus guidelines for FMD protocol and analysis) and participant characteristics/medical history from 5362 individuals (4–84 years; 2076 females). Healthy individuals (n=1403 [582 females]) were used to generate age-/sex-specific percentile curves. Subsequently, we included individuals with CVD risk factors, without overt disease (unmedicated n=3167 [1247 females] and medicated n=792 [247 females]). Multiple linear regression tested the relation of CVD risk factors (body mass index, blood pressure, cholesterol, diabetes, dyslipidemia, and smoking) with FMD. Healthy males showed a negative, curvilinear relation between FMD and age, while females revealed a negative linear relation that started higher but declined at a faster rate than males. Age- and sex-specific differences in FMD relate, at least partly, to baseline artery diameter. FMD was related to CVD risk factors in unmedicated (eg, systolic/diastolic blood pressure) and medicated individuals (eg, diabetes/dyslipidemia). Sex mediated some of these effects ( P

NEW FINDINGS What is the topic of this review? We have conducted a systematic review and meta-analysis on the current evidence for the effect of heat therapy on blood pressure and vascular function. What advances does it highlight? We found that heat therapy reduced mean arterial, systolic and diastolic blood pressure. We also observed that heat therapy improved vascular function, as assessed via brachial artery flow-mediated dilatation. Our results suggest that heat therapy is a promising therapeutic tool that should be optimized further, via mode and dose, for the prevention and treatment of cardiovascular disease risk factors. ABSTRACT Lifelong sauna exposure is associated with reduced cardiovascular disease risk. Recent studies have investigated the effect of heat therapy on markers of cardiovascular health. We aimed to conduct a systematic review with meta-analysis to determine the effects of heat therapy on blood pressure and indices of vascular function in healthy and clinical populations. Four databases were searched up to September 2020 for studies investigating heat therapy on outcomes including blood pressure and vascular function. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess the certainty of evidence. A total of 4522 titles were screened, and 15 studies were included. Healthy and clinical populations were included. Heat exposure was for 30-90 min, over 10-36 sessions. Compared with control conditions, heat therapy reduced mean arterial pressure [n = 4 studies; mean difference (MD): -5.86 mmHg, 95% confidence interval (CI): -8.63, -3.10; P

The endothelium is the single-cell monolayer that lines the entire vasculature. The endothelium has a barrier function to separate blood from organs and tissues but also has an increasingly appreciated role in anti-coagulation, vascular senescence, endocrine secretion, suppression of inflammation and beyond. In modern times, endothelial cells have been identified as the source of major endocrine and vaso-regulatory factors principally the dissolved lipophilic vosodilating gas, nitric oxide and the potent vascular constricting G protein receptor agonists, the peptide endothelin. The role of the endothelium can be conveniently conceptualized. Continued investigations of the mechanism of endothelial dysfunction will lead to novel therapies for cardiovascular disease. In this review, we discuss the impact of endothelial dysfunction on cardiovascular disease and assess the clinical relevance of endothelial dysfunction.

Background and Aim: Contrast-enhanced ultrasound (CEUS) measures of post-occlusion skeletal muscle microvascular responsiveness demonstrate the microvascular dysfunction associated with ageing and age-related disease. However, the accessibility of CEUS is limited by the need for intravenous administration of ultrasound contrast agents and sophisticated imaging analysis. Alternative methods are required for the broader assessment of microvascular dysfunction in research and clinical settings. Therefore, we aimed to evaluate the level of association and agreement between CEUS and near-infrared spectroscopy (NIRS)-derived measures of post-occlusion skeletal muscle microvascular responsiveness in older adults. Methods: During supine rest, participants (n=15, 67±11 years) underwent 5 minutes of thigh cuff-occlusion (200 mmHg). Post-occlusion CEUS measures of calf muscle microvascular responsiveness were made, including time to 95% peak acoustic intensity (TTP95 AI) and the rate of rise (slope AI). Simultaneous measures, including time to 95% peak oxygenated haemoglobin (TTP95 O2Hb) and slope O2Hb, were made using continuous-wave NIRS in the same muscle region. Results: There were strong correlations between TTP95 measures derived from CEUS and NIRS (r=0.834, p=

The UK population is growing, ageing and becoming increasingly inactive and unfit. Personalised and targeted exercise interventions are beneficial for ageing and the management of chronic and complex conditions. Increasing the uptake of effective exercise and physical activity (PA) interventions is vital to support a healthier society and decrease healthcare costs. Current strategies for exercise and PA at a population level mostly involve self-directed exercise pathways, delivered largely via the fitness industry. Even for those who opt-in and manage to achieve the current recommendations regarding minimum PA, this generic ‘one-size-fits-all’ approach often fails to demonstrate meaningful physiological and health benefits. Personalised exercise prescription and appropriate exercise testing, monitoring and progression of interventions for individuals with chronic disease should be provided by appropriately trained and recognised exercise healthcare professionals, educated in the cognate disciplines of exercise science (eg, physiology, biomechanics, motor control, psychology). This workforce has operated for >20 years in the Australian public and private healthcare systems. Accredited exercise physiologists (AEPs) are recognised allied health professionals, with demonstrable health and economic benefits. AEPs have knowledge of the risks and benefits of distinct forms of exercise, skills in the personalised prescription and optimal delivery of exercise, and competencies to support sustained PA behavioural change, based on the established scientific evidence. In this charter, we propose a road map for the training, accreditation and promotion of a clinical exercise physiology profession in the UK.

Intermittent claudication (IC) is pain or discomfort in the muscles of the calf, thigh or buttock that occurs during walking and is relieved by rest. It affects 4% of people over 60 years of age and is the most common symptom of peripheral arterial disease (PAD). For people with IC, the goals of treatment are twofold: (1) secondary prevention of cardiovascular disease through management of risk factors (eg, tobacco use, dyslipidaemia, diabetes, hypertension and physical inactivity); (2) improving functional status, with treatment options including exercise training, revascularisation and vasodilator therapy.1 In 2012, the UK’s National Institute for Health and Care Excellence published a clinical guideline on the diagnosis and …

Impairments in skeletal muscle microvascular function are frequently reported in patients with various cardiometabolic conditions for which older age is a risk factor. Whether aging per se predisposes the skeletal muscle to microvascular dysfunction is unclear. We used contrast‐enhanced ultrasound (CEU) to compare skeletal muscle microvascular perfusion responses to cuff occlusion and leg exercise between healthy young (n = 12, 26 ± 3 years) and older (n = 12, 68 ± 7 years) adults. Test–retest reliability of CEU perfusion parameters was also assessed. Microvascular perfusion (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after: (a) 5‐min of thigh‐cuff occlusion, and (b) 5‐min of submaximal intermittent isometric plantar‐flexion exercise (400 N) using CEU. Whole‐leg blood flow was measured using strain‐gauge plethysmography. Repeated measures were obtained with a 15‐min interval, and averaged responses were used for comparisons between age groups. There were no differences in post‐occlusion whole‐leg blood flow and muscle microvascular perfusion between young and older participants (p > .05). Similarly, total whole‐leg blood flow during exercise and post‐exercise peak muscle microvascular perfusion did not differ between groups (p > .05). The overall level of agreement between the test–retest measures of calf muscle perfusion was excellent for measurements taken at rest (intraclass correlation coefficient [ICC] 0.85), and in response to cuff occlusion (ICC 0.89) and exercise (ICC 0.95). Our findings suggest that healthy aging does not affect muscle perfusion responses to cuff‐occlusion and submaximal leg exercise. CEU muscle perfusion parameters measured in response to these provocation tests are highly reproducible in both young and older adults., We used contrast‐enhanced ultrasound (CEU) to compare skeletal muscle microvascular perfusion responses to cuff occlusion and leg exercise between healthy young (n = 12, 26 ± 3 years) and older (n = 12, 68 ± 7 years) adults. There were no differences in post‐occlusion whole‐leg blood flow and muscle microvascular perfusion between young and older participants (p > .05). Similarly, total whole‐leg blood flow during exercise and post‐exercise peak muscle microvascular perfusion did not differ between groups (p > .05).

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&ndash, 45 mm diameter, n = 33) and sex-matched control participants (n = 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-&alpha, ) 26.9 &plusmn, 3.3 vs. 15.5 &plusmn, 3.2 ng/mL, p &lt, 0.05, IL-6 3.2 &plusmn, 0.6 vs. 1.4 &plusmn, 0.3 ng/mL, p &lt, 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.

New Findings: What is the central question of the study? Cuff-occlusion duration may influence contrast-enhanced ultrasound (CEUS) assessments of skeletal muscle microvascular blood flow responsiveness: what are the effects of 1, 3 and 5 min cuff-occlusion on the magnitude and reliability of calf muscle microvascular blood flow responsiveness in older adults? What is the main finding and its importance? Calf muscle microvascular blood flow responsiveness was enhanced following 5 min cuff-occlusion compared with 1 min. The reliability of post-occlusion CEUS measurements was also improved following 5 min occlusion. The use of a standardized 5 min occlusion period should therefore be considered in future studies and clinical practice. Abstract: Contrast-enhanced ultrasound (CEUS) is increasingly used in assessments of skeletal muscle microvascular blood flow responsiveness. In response to limb cuff-occlusion, some studies have reported significant impairments in CEUS measurements of microvascular blood flow in older adults with cardiovascular or metabolic disease, whereas others have failed to detect significant between-group differences, which has brought the reliability of the technique into question. In the absence of a standardized CEUS protocol, there is variance in the duration of cuff-occlusion used, which is likely to influence post-occlusion measurements of muscle microvascular blood flow. We aimed to determine the effect of cuff-occlusion duration by comparing the magnitude and reliability of CEUS measurements of calf muscle microvascular blood flow responsiveness in older adults (n = 15, 67 ± 11 years) following 1, 3 and 5 min occlusion periods. Microvascular blood flow (= microvascular volume × microvascular velocity) within the calf muscle was measured using real-time destruction–replenishment CEUS. Measurements were made following thigh cuff-occlusion (200 mmHg) periods of 1, 3 and 5 min in a random order. Microvascular blood flow was higher following 3 min (3.71 ± 1.46 aU s−1) and 5 min (3.47 ± 1.48 aU s−1) compared with 1 min (2.42 ± 1.27 aU s−1, P = 0.002), which corresponded with higher microvascular volumes after 3 and 5 min compared with 1 min. Reliability was good following 5 min (intraclass correlation coefficient (ICC) 0.49) compared with poor following 1 min (ICC 0.34) and 3 min (ICC 0.35). This study demonstrates that the magnitude and reliability of calf muscle microvascular responsiveness is enhanced using a 5 min cuff-occlusion protocol compared with 1 min in older adults.

ObjectivesTo assess how the early stages of National governments Coronavirus disease (COVID-19) containment strategies impacted upon the physical activity, mental health and well-being of adults in the UK, Ireland, New Zealand and AustraliaDesignObservational, cross-sectionalSettingOnline survey disseminated in the UK, Ireland, New Zealand and Australia within the first 2-6 weeks of government mandated COVID-19 restrictionsParticipantsAdults (n = 8,425; 44.5 ± 14.8 y), ≥ 18 y who were residing in the surveyed countriesMain outcome measuresStages of Change scale for exercise behaviour change, International Physical Activity Questionnaire (short-form), World Health Organisation-5 Well-being Index and the Depression Anxiety and Stress Scale-9ResultsParticipants who reported a negative change in exercise behaviour between pre- and during the early COVID-19 restrictions demonstrated poorer mental health and well-being compared to those who had either a positive change- or no change in their exercise behaviour (ppppConclusionThe COVID-19 restrictions have differentially impacted upon the physical activity habits of individuals based upon their age and sex, and therefore have important implications for international policy and guideline recommendations. Public health interventions that encourage physical activity should target specific groups (e.g., men, young adults) who are most vulnerable to the negative effects of physical distancing and/or self-isolation.

BackgroundIncomplete restoration of myocardial blood flow (MBF) is reported in up to 30% of ST-segment elevation myocardial infarction (STEMI) despite prompt mechanical revascularization. Experimental hyperinsulinemic euglycemia (HE) increases MBF reserve (MBFR). If fully exploited, this effect may also improve MBF to ischemic myocardium. Using insulin-dextrose infusions to induce HE, we conducted four experiments to determine (1) how insulin infusion duration, dose, and presence of insulin resistance affect MBFR response; and (2) the effect of an insulin-dextrose infusion given immediately following revascularization of STEMI on myocardial perfusion.MethodsThe MBFR was determined using myocardial contrast echocardiography. Experiment 1 (insulin duration): 12 participants received an insulin-dextrose or saline infusion for 120 minutes. MBFR was measured at four time intervals during infusion. Experiment 2 (insulin dose): 22 participants received one of three insulin doses (0.5, 1.5, 3.0 mU/kg/minute) for 60 minutes. Baseline and 60-minute MBFRs were determined. Experiment 3 (insulin resistance): five metabolic syndrome and six type 2 diabetes (T2DM) participants received 1.5 mU/kg/minute of insulin-dextrose for 60 minutes. Baseline and 60-minute MBFRs were determined. Experiment 4 (STEMI): following revascularization for STEMI, 20 patients were randomized to receive either 1.5 mU/kg/minute insulin-dextrose infusion for 120 minutes or standard care. Myocardial contrast echocardiography was performed at four time intervals to quantify percentage contrast defect length.ResultsExperiment 1: MBFR increased with time through to 120 minutes in the insulin-dextrose group and did not change in controls. Experiment 2: compared with baseline, MBFR increased in the 1.5 (2.42 ± 0.39 to 3.25 ± 0.77, P = .002), did not change in the 0.5, and decreased in the 3.0 (2.64 ± 0.25 to 2.16 ± 0.33, P = .02) mU/kg/minute groups. Experiment 3: compared with baseline, MBFR increase was only borderline significant in metabolic syndrome and T2DM participants (1.98 ± 0.33 to 2.59 ± 0.45, P = .04, and 1.67 ± 0.35 to 2.14 ± 0.21, P = .05). Experiment 4: baseline percentage contrast defect length was similar in both groups but with insulin decreased with time and was significantly lower than in controls at 60 minutes (2.8 ± 5.7 vs 13.7 ± 10.6, P = .02).ConclusionsPresence of T2DM, insulin infusion duration, and dose are important determinants of the MBFR response to HE. When given immediately following revascularization for STEMI, insulin-dextrose reduces perfusion defect size at one hour. Hyperinsulinemic euglycemia may improve MBF following ischemia, but further studies are needed to clarify this.

Introduction Aging is associated with impaired cerebrovascular blood flow and function, attributed to reduced vasodilatory capacity of the cerebrovascular network. Older adults may also have an impaired relationship between changes in blood pressure and cerebral blood flow; however, previous reports conflict. This study aimed to compare the blood pressure and cerebral blood flow responses to both repeated and sustained stand‐to‐sit transitions in young and older adults, and to assess the relationship with cerebrovascular reactivity. Methods In 20 young (age: 24 ± 4 years) and 20 older (age: 71 ± 7 years) adults we compared middle cerebral artery flow velocity (MCAv), end‐tidal partial pressure of carbon dioxide (PETCO2), and blood pressure (mean arterial blood pressure [MAP]) during repeated stand‐to‐sit (10 s standing and 10 s sitting) and sustained stand‐to‐sit (3 min standing followed by 2 min sitting) transitions. Cerebrovascular reactivity to changes in carbon dioxide levels was assessed using a repeated breath‐hold test. Results The % change in MCAv per % change in MAP (%∆MCAv/%∆MAP) was higher in the older adults than in the young adults during repeated stand‐to‐sit transitions. During the sustained protocol the %∆MCAv/%∆MAP response was similar in both age groups. A high %∆MCAv/%∆MAP response during the repeated stand‐to‐sit protocol was associated with low cerebrovascular reactivity to CO2 (r = −.39; p, Aging and age‐related cerebrovascular diseases are associated with impaired cerebrovascular function. The novel finding of this study is that older adults showed higher pressure–flow responses during repeated stand–sit transitions compared to younger adults, and that a high pressure–flow response was associated with low cerebrovascular reactivity to CO2. These results suggest that impaired vascular function and increased arterial stiffness may contribute to the pressure–flow responses observed in the older adults.

Peripheral artery disease (PAD) is caused by atherosclerotic narrowing of the arteries supplying the lower limbs often resulting in intermittent claudication, evident as pain or cramping while walking. Supervised exercise training elicits clinically meaningful benefits in walking ability and quality of life. Walking is the modality of exercise with the strongest evidence and is recommended in several national and international guidelines. Alternate forms of exercise such as upper- or lower-body cycling may be used, if required by certain patients, although there is less evidence for these types of programmes. The evidence for progressive resistance training is growing and patients can also engage in strength-based training alongside a walking programme. For those unable to attend a supervised class (strongest evidence), home-based or ‘self-facilitated’ exercise programmes are known to improve walking distance when compared to simple advice. All exercise programmes, independent of the mode of delivery, should be progressive and individually prescribed where possible, considering disease severity, comorbidities and initial exercise capacity. All patients should aim to accumulate at least 30 min of aerobic activity, at least three times a week, for at least 3 months, ideally in the form of walking exercise to near-maximal claudication pain.

The aim of this study was to determine the effect of age on the relationship between cerebrovascular function and the neural bases of sustained attention. Twenty-seven healthy young adults (aged 18–30 years) and 24 older adults (60–75 years) underwent assessments of cerebrovascular function and sustained attention. Blood flow velocity of the middle cerebral artery was assessed via Transcranial Doppler Ultrasound, during seated rest, in response to hypocapnic breathing (cerebrovascular reactivity) and during a repeated sit-to-stand procedure (pressure-flow response). Attentional processing was assessed using the N2 and P3 components of the event-related potential during a two-tone auditory oddball task. Poorer pressure-flow responses were significantly associated with reductions in N2 and P3 amplitude in the old group (b = −0.50, p = .029 and b = −0.46, p = .045), but not the young group. These results suggest that alterations in the brain’s capacity to combat reductions in perfusion pressure are associated with age-related differences in attentional processing, supporting the hypothesis that cerebrovascular hemodynamic disturbances play a role in age-related cognitive decline.

Background: Assessment of endothelial function using brachial artery flow-mediated dilation (FMD) predicts future cardiovascular disease (CVD) risk. However, poor adherence to protocol guidelines and lack of reference values hinders widespread FMD use. This study established age- and sex-specific reference intervals for brachial artery FMD in healthy individuals and examined the relation with CVD risk factors. Methods: Collected according to expert-consensus guidelines, we combined brachial artery FMD and subject characteristics/medical history from 5,362 individuals (4–84 years; 2,076 females). We first examined healthy individuals (n = 1,403 [582 females]) to generate age-/sex-specific percentile curves. Subsequently, we included subjects with CVD risk factors but without disease (un-medicated n = 3,167 [1,247 females], and medicated n = 792 [247 females]). Multiple linear regression tested the relation of CVD risk factors with FMD. Results: Healthy men showed a negative, curvilinear relation between FMD and age, whilst females revealed a linear relation that started higher, but declined at a faster rate. Age-/sex-related differences in FMD, at least partly, relate to baseline artery diameter. FMD was affected by CVD risk factors in un-medicated (e.g. systolic-/diastolic blood pressure, diabetes) and medicated subjects (e.g. dyslipidaemia). Importantly, sex mediated these effects (p < 0.05), with (supra) normalisation of FMD in medicated men, but not in women (except for blood pressure). Conclusion: Sex alters the age-related decline in FMD, which is partly explained through differences in artery diameter. Sex also altered the effect of some CVD risk factors and medication on FMD. This work improves interpretation and future use of the FMD technique when strictly adhering to FMD protocol guidelines.

Peripheral arterial disease (PAD) is characterized by stenosis and occlusion of the lower limb arteries. Although leg blood flow is limited in PAD, it remains unclear whether skeletal muscle microvascular perfusion is affected. We compared whole leg blood flow and calf muscle microvascular perfusion after cuff occlusion and submaximal leg exercise between patients with PAD ( n = 12, 69 ± 9 yr) and healthy age-matched control participants ( n = 12, 68 ± 7 yr). Microvascular blood flow (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after the following: 1) 5 min of thigh-cuff occlusion, and 2) a 5-min bout of intermittent isometric plantar-flexion exercise (400 N) using real-time contrast-enhanced ultrasound. Whole leg blood flow was measured after thigh-cuff occlusion and during submaximal plantar-flexion exercise using strain-gauge plethysmography. Postocclusion whole leg blood flow and calf muscle microvascular perfusion were lower in patients with PAD than control participants, and these parameters were strongly correlated ( r = 0.84, P < 0.01). During submaximal exercise, total whole leg blood flow and vascular conductance were not different between groups. There were also no group differences in postexercise calf muscle microvascular perfusion, although microvascular blood volume was higher in patients with PAD than control participants (12.41 ± 6.98 vs. 6.34 ± 4.98 arbitrary units, P = 0.03). This study demonstrates that the impaired muscle perfusion of patients with PAD during postocclusion hyperemia is strongly correlated with disease severity and is likely mainly determined by the limited conduit artery flow. In response to submaximal leg exercise, microvascular flow volume was elevated in patients with PAD, which may reflect a compensatory mechanism to maintain muscle perfusion and oxygen delivery during recovery from exercise. NEW & NOTEWORTHY This study suggests that peripheral arterial disease (PAD) has different effects on the microvascular perfusion responses to cuff occlusion and submaximal leg exercise. Patients with PAD have impaired microvascular perfusion after cuff occlusion, similar to that previously reported after maximal exercise. In response to submaximal exercise, however, the microvascular flow volume response was elevated in patients with PAD compared with control. This finding may reflect a compensatory mechanism to maintain perfusion and oxygen delivery during recovery from exercise.

Purpose: To explore the influence of body composition on thermal responses to cold-water immersion (CWI) and the recovery of exercise performance. Methods: Male subjects were stratified into 2 groups: low fat (LF; n = 10) or high fat (HF; n = 10). Subjects completed a high-intensity interval test (HIIT) on a cycle ergometer followed by a 15-min recovery intervention (control [CON] or CWI). Core temperature (Tc), skin temperature, and heart rate were recorded continuously. Performance was assessed at baseline, immediately post-HIIT, and 40 min postrecovery using a 4-min cycling time trial (TT), countermovement jump (CMJ), and isometric midthigh pull (IMTP). Perceptual measures (thermal sensation [TS], total quality of recovery [TQR], soreness, and fatigue) were also assessed. Results: Tc and TS were significantly lower in LF than in HF from 10 min (Tc, LF 36.5°C ± 0.5°C, HF 37.2°C ± 0.6°C; TS, LF 2.3 ± 0.5 arbitrary units [a.u.], HF 3.0 ± 0.7 a.u.) to 40 min (Tc, LF 36.1°C ± 0.6°C, HF 36.8°C ±0.7°C; TS, LF 2.3 ± 0.6 a.u., HF 3.2 ± 0.7 a.u.) after CWI (P P = .01); however, no differences were observed between HF (6.9% ±5.7%) and LF (5.4% ± 5.2%) with CON. No significant differences were observed between groups for CMJ, IMTP, TQR, soreness, or fatigue in either condition. Conclusion: Body composition influences the magnitude of Tc change during and after CWI. In addition, CWI enhanced performance recovery in the HF group only. Therefore, body composition should be considered when planning CWI protocols to avoid overcooling and maximize performance recovery.

Cardiovascular disease is associated with increased risk for cognitive decline and dementia, but it is unclear whether this risk varies across disease states or occurs in the absence of symptomatic stroke. To examine the evidence of increased risk for cognitive decline and dementia following non-stroke cardiovascular disease we conducted two independent meta-analyses in accordance with PRISMA guidelines. The first review examined cardiovascular diagnoses (atrial fibrillation, congestive heart failure, periphery artery disease and myocardial infarction) while the second review assessed the impact of atherosclerotic burden (as indicated by degree of stenosis, calcification score, plaque morphology or number of plaques). Studies eligible for review longitudinally assessed risk for clinically significant cognitive decline and/or dementia and excluded stroke and cognitive impairment at baseline. Summary statistics were computed via the inverse variance weighted method, utilising Cox Proportional Hazards data (Hazard Ratios, HR). Both atrial fibrillation (n = 5, HR = 1.26, 95% CI [1.12, 1.43]) and severe atherosclerosis (n = 4, HR = 1.59, 95% CI [1.12, 2.26]) emerged as significant risk factors for cognitive decline and/or dementia. A small set of studies reviewed, insufficient for meta-analysis, examining congestive heart failure, peripheral artery disease and myocardial infarction suggested that these conditions may also be associated with an increased risk of cognitive decline/dementia. In the absence of stroke, patients with atrial fibrillation or generalised atherosclerosis are at heightened risk for cognitive deterioration. Nonetheless, this paper highlights the need for methodologically rigorous and prospective investigation of the relationship between CVD and dementia.