Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation.

Brain function critically depends on a close matching between metabolic demands, appropriate delivery of oxygen and nutrients, and removal of cellular waste. This matching requires continuous regulation of cerebral blood flow (CBF), which can be categorized into four broad topics: 1) autoregulation, which describes the response of the cerebrovasculature to changes in perfusion pressure; 2) vascular reactivity to vasoactive stimuli [including carbon dioxide (CO2)]; 3) neurovascular coupling (NVC), i.e., the CBF response to local changes in neural activity (often standardized cognitive stimuli in humans); and 4) endothelium-dependent responses. This review focuses primarily on autoregulation and its clinical implications. To place autoregulation in a more precise context, and to better understand integrated approaches in the cerebral circulation, we also briefly address reactivity to CO2 and NVC. In addition to our focus on effects of perfusion pressure (or blood pressure), we describe the impact of select stimuli on regulation of CBF (i.e., arterial blood gases, cerebral metabolism, neural mechanisms, and specific vascular cells), the interrelationships between these stimuli, and implications for regulation of CBF at the level of large arteries and the microcirculation. We review clinical implications of autoregulation in aging, hypertension, stroke, mild cognitive impairment, anesthesia, and dementias. Finally, we discuss autoregulation in the context of common daily physiological challenges, including changes in posture (e.g., orthostatic hypotension, syncope) and physical activity.

Relationship of device measured physical activity type and posture with cardiometabolic health markers: pooled dose-response associations from the Prospective Physical Activity, Sitting and Sleep Consortium.

AIMS/HYPOTHESIS: The aim of this study was to examine the dose-response associations of device-measured physical activity types and postures (sitting and standing time) with cardiometabolic health. METHODS: We conducted an individual participant harmonised meta-analysis of 12,095 adults (mean ± SD age 54.5±9.6 years; female participants 54.8%) from six cohorts with thigh-worn accelerometry data from the Prospective Physical Activity, Sitting and Sleep (ProPASS) Consortium. Associations of daily walking, stair climbing, running, standing and sitting time with a composite cardiometabolic health score (based on standardised z scores) and individual cardiometabolic markers (BMI, waist circumference, triglycerides, HDL-cholesterol, HbA1c and total cholesterol) were examined cross-sectionally using generalised linear modelling and cubic splines. RESULTS: We observed more favourable composite cardiometabolic health (i.e. z score <0) with approximately 64 min/day walking (z score [95% CI] -0.14 [-0.25, -0.02]) and 5 min/day stair climbing (-0.14 [-0.24, -0.03]). We observed an equivalent magnitude of association at 2.6 h/day standing. Any amount of running was associated with better composite cardiometabolic health. We did not observe an upper limit to the magnitude of the dose-response associations for any activity type or standing. There was an inverse dose-response association between sitting time and composite cardiometabolic health that became markedly less favourable when daily durations exceeded 12.1 h/day. Associations for sitting time were no longer significant after excluding participants with prevalent CVD or medication use. The dose-response pattern was generally consistent between activity and posture types and individual cardiometabolic health markers. CONCLUSIONS/INTERPRETATION: In this first activity type-specific analysis of device-based physical activity, ~64 min/day of walking and ~5.0 min/day of stair climbing were associated with a favourable cardiometabolic risk profile. The deleterious associations of sitting time were fully attenuated after exclusion of participants with prevalent CVD and medication use. Our findings on cardiometabolic health and durations of different activities of daily living and posture may guide future interventions involving lifestyle modification.

Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli.

On the 400th anniversary of Harvey's Lumleian lectures, this review focuses on "hemodynamic" forces associated with the movement of blood through arteries in humans and the functional and structural adaptations that result from repeated episodic exposure to such stimuli. The late 20th century discovery that endothelial cells modify arterial tone via paracrine transduction provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the interrelationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions, and the implications for human health. Exercise modifies blood flow, luminal shear stress, arterial pressure, and tangential wall stress, all of which can transduce changes in arterial function, diameter, and wall thickness. There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute to the well-established decrease in cardiovascular risk attributed to physical activity.

Impact of Hypertension on the Dose-Response Association Between Physical Activity and Stroke: A Cohort Study.

BACKGROUND: Regular physical activity is associated with a reduced stroke risk. However, this relationship might be attenuated in the presence of hypertension and antihypertensive medication use. We examined the dose-response relationship between physical activity and stroke in normotensive and hypertensive individuals. METHODS: A Dutch population-based cohort including 139 930 individuals (41% men; mean age, 44±13) was performed (median follow-up, 6.75 years). Participants were stratified at baseline as hypertensive (44%) or normotensive (56%) and categorized into quartiles of the lowest (Q1) to the highest (Q4) moderate-to-vigorous, self-reported physical activity. The primary outcome was incident stroke (fatal and nonfatal). Cox regression estimated hazard ratios and 95% CIs. The main analyses were stratified on baseline blood pressure and adjusted for confounders. Hypertensives were stratified into medicated (21%) or non-medicated (79%). RESULTS: Compared with Q1, adjusted hazard ratios were 0.87 (0.69-1.10; P=0.23), 0.75 (0.59-0.95; P=0.02), and 0.94 (0.74-1.20; P=0.64) for Q2 to Q4, respectively in the total population. Hazard ratios for normotensives were 0.79 (0.50-1.25; P=0.32), 0.75 (0.48-1.18; P=0.22), 0.97 (0.62-1.51; P=0.90) for Q2 to Q4, respectively. In hypertensives, hazard ratios were 0.89 (0.68-1.17; P=0.41), 0.74 (0.56-0.98; P=0.03), 0.92 (0.69-1.23; P=0.56) for Q2 to Q4, respectively. There was no significant interaction between hypertension status for the relation between physical activity and stroke risk. The stratified analysis revealed a smaller benefit of moderate-to-vigorous physical activity in medicated hypertensives compared with nonmedicated hypertensives, but no significant interaction effect was found. CONCLUSIONS: Regular moderate-to-vigorous physical activity is beneficial for stroke risk reduction (Q3 compared with Q1), which is not affected by hypertension. Antihypertensive medication may be associated with a smaller benefit of moderate-to-vigorous physical activity on the risk of stroke, but further research is warranted.

Single and 7-day handgrip and squat exercise prevents endothelial ischemia-reperfusion injury in individuals with cardiovascular disease risk factors.

Whole body exercise provides protection against endothelial ischemia-reperfusion (IR) injury. In this crossover study, we examined the effects of 1) single bout of local exercise (handgrip, squats) on endothelial responses to IR, and 2) if 7 days of daily local exercise bolsters these effects in individuals with cardiovascular disease (CVD) risk factors. Fifteen participants (9 women, 58 ± 5 yr, ≥2 CVD risk factors) attended the laboratory for six visits. Subsequent to familiarization (visit 1), during visit 2 (control) brachial artery flow-mediated dilation (FMD) was measured before and after IR (15-min upper-arm ischemia, 15-min reperfusion). One week later, participants were randomized to 4 × 5-min unilateral handgrip (50% maximal voluntary contraction, 25 rpm) or squat exercises (15 rpm), followed by IR plus FMD measurements. Subsequently, home-based exercise was performed (6 days), followed by another visit to the laboratory for the IR protocol plus FMD measurements (18-24 h after the last exercise bout). After a 2-wk washout period, procedures were repeated with the alternative exercise mode. For a single exercise bout, we found a significant IR injury × exercise mode interaction (P < 0.01) but no main effect of injury (P = 0.08) or condition (P = 0.61). A lower post-IR FMD was evident after control (pre-IR: 4.3 ± 2.1% to post-IR: 2.9 ± 1.9%, P < 0.01) but not after handgrip (pre-IR: 3.8 ± 1.6% to post-IR: 3.4 ± 1.5%, P = 0.31) or squats (pre-IR: 3.9 ± 1.8% to post-IR: 4.0 ± 1.9%, P = 0.74). After 7 days of daily exercise, we found no change in FMD post-IR following handgrip (pre-IR: 4.3 ± 1.9% to post-IR: 4.7 ± 3.2%) or squats (pre-IR: 3.7 ± 2.1% to post-IR: 4.7 ± 3.0%, P > 0.05). Single bouts of dynamic, local exercise (handgrip, squats) provide remote protection against endothelial IR-induced injury in individuals with CVD risk factors, with 1-wk daily, home-based exercise preserving these effects for up to 24 h following the last exercise bout.NEW & NOTEWORTHY We show that single bouts of dynamic handgrip and squat exercise provide remote protection against endothelial ischemia-reperfusion (IR)-induced injury in individuals with cardiovascular disease (CVD) risk factors, with 1-wk daily, home-based exercise preserving these effects for up to 24 h following the last exercise bout.

The Hypoxia Response Pathway: A Potential Intervention Target in Parkinson's Disease?

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which only symptomatic treatments are available. Both preclinical and clinical studies suggest that moderate hypoxia induces evolutionarily conserved adaptive mechanisms that enhance neuronal viability and survival. Therefore, targeting the hypoxia response pathway might provide neuroprotection by ameliorating the deleterious effects of mitochondrial dysfunction and oxidative stress, which underlie neurodegeneration in PD. Here, we review experimental studies regarding the link between PD pathophysiology and neurophysiological adaptations to hypoxia. We highlight the mechanistic differences between the rescuing effects of chronic hypoxia in neurodegeneration and short-term moderate hypoxia to improve neuronal resilience, termed "hypoxic conditioning". Moreover, we interpret these preclinical observations regarding the pharmacological targeting of the hypoxia response pathway. Finally, we discuss controversies with respect to the differential effects of hypoxia response pathway activation across the PD spectrum, as well as intervention dosing in hypoxic conditioning and potential harmful effects of such interventions. We recommend that initial clinical studies in PD should focus on the safety, physiological responses, and mechanisms of hypoxic conditioning, as well as on repurposing of existing pharmacological compounds. © 2023 International Parkinson and Movement Disorder Society.

A cardiac-rehab behaviour intervention to reduce sedentary time in coronary artery disease patients: the SIT LESS randomized controlled trial.

BACKGROUND: High sedentary times (ST) is highly prevalent in patients with coronary artery disease (CAD), highlighting the need for behavioural change interventions that effectively reduce ST. We examined the immediate and medium-term effect of the SIT LESS intervention on changes in ST among CAD patients enrolled in cardiac rehabilitation (CR). METHODS: CAD patients participating in CR at 2 regional hospitals were included in this randomized controlled trial (1:1, stratified for gender and hospital). The control group received CR, whereas SIT LESS participants additionally received a 12-week hybrid behaviour change intervention. The primary outcome was the change in accelerometer-derived ST from pre-CR to post-CR and 3 months post-CR. Secondary outcomes included changes in ST and physical activity characteristics, subjective outcomes, and cardiovascular risk factors. A baseline constrained linear mixed-model was used. RESULTS: Participants (23% female; SIT LESS: n = 108, control: n = 104) were 63 ± 10 years. Greater ST reductions were found for SIT LESS compared to control post-CR (-1.7 (95% confidence interval (CI): -2.0; -1.4) versus - 1.1 (95% CI: -1.4; -0.8) h/day, pinteraction=0.009), but not at 3 months post-CR (pinteraction=0.61). Besides, larger light-intensity physical activity (LIPA) increases were found for SIT LESS compared to control post-CR (+ 1.4 (95% CI: +1.2; +1.6) versus + 1.0 (95% CI: +0.8; +1.3) h/day, pinteraction=0.020). Changes in other secondary outcomes did not differ among groups. CONCLUSION: SIT LESS transiently reduced ST and increased LIPA, but group differences were no longer significant 3 months post-CR. These findings highlight the challenge to induce sustainable behaviour changes in CAD patients without any continued support. TRIAL REGISTRATION: Netherlands Trial Register: NL9263. Registration Date: 24 February 2021.

Randomized controlled trial of intermittent hypoxia in Parkinson's disease: study rationale and protocol.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD. METHODS/DESIGN: This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction. DISCUSSION: This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05948761 (registered June 20th, 2023).

Exercise-based cardiac rehabilitation in stable angina pectoris: a narrative review on current evidence and underlying physiological mechanisms.

Stable angina pectoris (SAP) is a prevalent condition characterised by a high disease burden. Based on recent evidence, the need for revascularisation in addition to optimal medical treatment to reduce mortality and re-events is heavily debated. These observations may be explained by the fact that revascularisation is targeted at the local flow-limiting coronary artery lesion, while the aetiology of SAP relates to the systemic, inflammatory process of atherosclerosis, causing generalised vascular dysfunction throughout the entire vascular system. Moreover, cardiovascular events are not solely caused by obstructive plaques but are also associated with plaque burden and high-risk plaque features. Therefore, to reduce the risk of cardiovascular events and angina, and thereby improve quality of life, alternative therapeutic approaches to revascularisation should be considered, preferably targeting the cardiovascular system as a whole with a physiological approach. Exercise-based cardiac rehabilitation fits this description and is a promising strategy as a first-line treatment in addition to optimal medical treatment. In this review, we discuss the role of exercise-based cardiac rehabilitation in SAP in relation to the underlying physiological mechanisms, we summarise the existing evidence and highlight future directions.

No insulin degludec dose adjustment required after aerobic exercise for people with type 1 diabetes: the ADREM study.

AIMS/HYPOTHESIS: It is generally recommended to reduce basal insulin doses after exercise to reduce the risk of post-exercise nocturnal hypoglycaemia. Based on its long t½, it is unknown whether such adjustments are required or beneficial for insulin degludec. METHODS: The ADREM study (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) was a randomised controlled, crossover study in which we compared 40% dose reduction (D40), or postponement and 20% dose reduction (D20-P), with no dose adjustment (CON) in adults with type 1 diabetes at elevated risk of hypoglycaemia, who performed a 45 min aerobic exercise test in the afternoon. All participants wore blinded continuous glucose monitors for 6 days, measuring the incidence of (nocturnal) hypoglycaemia and subsequent glucose profiles. RESULTS: We recruited 18 participants (six women, age 38 ± 13 years, HbA1c 56 ± 8 mmol/mol [7.3 ± 0.8%], mean ± SD). Time below range (i.e. glucose <3.9 mmol/l) the night after the exercise test was generally low and occurrence did not differ between the treatment regimens. During the subsequent whole day, time below range was lower for D40 compared with CON (median [IQR], 0 [0-23] vs 18 [0-55] min, p=0.043), without differences in the number of hypoglycaemic events. Time above range (i.e. glucose >10 mmol/l) was greater for D20-P vs CON (mean ± SEM, 584 ± 81 vs 364 ± 66 min, p=0.001) and D40 (385 ± 72 min, p=0.003). CONCLUSIONS/INTERPRETATION: Post-exercise adjustment of degludec does not mitigate the risk of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. Although reducing degludec reduced next-day time below range, this did not translate into fewer hypoglycaemic events, while postponing degludec should be avoided because of increased time above range. Altogether, these data do not support degludec dose adjustment after a single exercise bout. TRIAL REGISTRATION: EudraCT number 2019-004222-22 FUNDING: The study was funded by an unrestricted grant from Novo Nordisk, Denmark.

Long-term cardiovascular health status and physical functioning of nonhospitalized patients with COVID-19 compared with non-COVID-19 controls.

Coronavirus disease 2019 (COVID-19) is reported to have long-term effects on cardiovascular health and physical functioning, even in the nonhospitalized population. The physiological mechanisms underlying these long-term consequences are however less well described. We compared cardiovascular risk factors, arterial stiffness, and physical functioning in nonhospitalized patients with COVID-19, at a median of 6 mo postinfection, versus age- and sex-matched controls. Cardiovascular risk was assessed using blood pressure and biomarker concentrations (amino-terminal pro-B-type-natriuretic-peptide, high-sensitive cardiac troponin I, C-reactive protein), and arterial stiffness was assessed using carotid-femoral pulse wave velocity. Physical functioning was evaluated using accelerometry, handgrip strength, gait speed and questionnaires on fatigue, perceived general health status, and health-related quality of life (hrQoL). We included 101 former patients with COVID-19 (aged 59 [interquartile range, 55-65] yr, 58% male) and 101 controls. At 175 [126-235] days postinfection, 32% of the COVID-19 group reported residual symptoms, notably fatigue, and 7% required post-COVID-19 care. We found no differences in blood pressure, biomarker concentrations, or arterial stiffness between both groups. Former patients with COVID-19 showed a higher handgrip strength (43 [33-52] vs. 38 [30-48] kg, P = 0.004) and less sleeping time (8.8 [7.7-9.4] vs. 9.8 [8.9-10.3] h/day, P < 0.001) and reported fatigue more often than controls. Accelerometry-based habitual physical activity levels, gait speed, perception of general health status, and hrQoL were not different between groups. In conclusion, one in three nonhospitalized patients with COVID-19 reports residual symptoms at a median of 6 mo postinfection, but we were unable to relate these symptoms to increases in cardiovascular risk factors, arterial stiffness, or physical dysfunction.NEW & NOTEWORTHY We examined cardiovascular and physical functioning outcomes in nonhospitalized patients with COVID-19, at a median of 6 mo postinfection. When compared with matched controls, minor differences in physical functioning were found, but objective measures of cardiovascular risk and arterial stiffness did not differ between groups. However, one in three former patients with COVID-19 reported residual symptoms, notably fatigue. Follow-up studies should investigate the origins of residual symptoms and their long-term consequences in former, nonhospitalized patients with COVID-19.

Exercise-induced release of cardiac troponin is attenuated with repeated bouts of exercise: impact of cardiovascular disease and risk factors.

Prolonged exercise can induce cardiac troponin release. As single bouts of exercise may protect against cardiac injury, we explored the hypothesis that the magnitude of exercise-induced release of troponin attenuates upon successive days of exercise. We also examined whether effects of successive exercise bouts differ between healthy participants and individuals with cardiovascular risk factors (CVRFs) and established cardiovascular disease (CVD). We examined cardiac troponin I (cTnI) concentrations from whole venous blood samples collected from the antecubital vein (10 mL) in 383 participants (61 ± 14 yr) at rest and immediately following four consecutive days of long-distance walking (30-50 km/day). Participants were classified as either healthy (n = 222), CVRF (n = 75), or CVD (n = 86). Baseline cTnI concentrations were significantly higher in participants with CVD and CVRF compared with healthy (P < 0.001). Exercise-induced elevations in cTnI were observed in all groups following all days of walking compared with baseline (P < 0.001). Tobit regression analysis on absolute cTnI concentrations revealed a significant day × group interaction (P = 0.04). Following day 1 of walking, post hoc analysis showed that exercise-induced elevations in cTnI attenuated on subsequent days in healthy and CVRF, but not in CVD. Odds ratios for incident cTnI concentrations above the upper reference limit were significantly higher compared with baseline on day 1 for healthy participants (4.90 [95% CI, 1.58-15.2]) and participants with CVD (14.9 [1.86-125]) and remained significantly higher than baseline on all subsequent days in CVD. The magnitude of postexercise cTnI concentrations following prolonged walking exercise significantly declines upon repeated days of exercise in healthy individuals and those with CVRF, whereas this decline is not present in patients with CVD.NEW & NOTEWORTHY We show the magnitude of postexercise cardiac troponin concentrations following prolonged walking exercise significantly declines upon repeated days of exercise in healthy individuals and those with cardiovascular risk factors, while this decline is not present in patients with established cardiovascular disease.

Handgrip exercise in patients scheduled for cardiac surgery to attenuate troponin release: a feasibility study.

Cardiac surgery, including surgical aortic valve repair (SAVR) and coronary artery bypass grafting (CABG), are associated with ischemia-reperfusion (I/R) injury. Single bouts of exercise, including handgrip exercise, may protect against I/R injury. This study explored 1) the feasibility of daily handgrip exercise in the week before SAVR and/or CABG and 2) its impact on cardiac I/R injury, measured as postoperative cardiac troponin-T (cTnT) release. Sixty-five patients undergoing elective SAVR and/or CABG were randomized to handgrip exercise + usual care (intervention, n = 33) or usual care alone (control, n = 32). Handgrip exercise consisted of daily 4 × 5-min handgrip exercise (30% maximal voluntary contraction) for 2-7 days before cardiac surgery. Feasibility was assessed using validated questionnaires. Postoperative cTnT release was assessed at 0, 6, 12, 18, and 24 h [primary outcome area under the curve (cTnTAUC)]. Most patients (93%) adhered to handgrip exercise and 77% was satisfied with this intervention. Handgrip exercise was associated with lower cTnTAUC (402,943 ± 225,206 vs. 473,300 ± 232,682 ng · min/L), which is suggestive of a medium effect size (Cohen's d 0.31), and lower cTnTpeak (313 [190-623] vs. 379 [254-699] ng/L) compared with controls. We found that preoperative handgrip exercise is safe and feasible for patients scheduled for SAVR and/or CABG and is associated with a medium effect size to reduce postoperative cardiac I/R injury. This warrants future studies to assess the potential clinical impact of exercise protocols before cardiac surgery.NEW & NOTEWORTHY Daily handgrip exercise in the week before elective cardiac surgery is safe and feasible. Handgrip exercise is associated with a medium effect size for less troponin-T release. Future larger-sized studies are warranted to explore the impact of (handgrip) exercise prior to cardiac surgery on clinical outcomes and direct patient benefits.

VEGFA rs2010963 GG genotype is associated with superior adaptations to resistance versus endurance training in the same group of healthy, young men.

PURPOSE: We used a within-subject, cross-over study to determine the relationship between the intra-individual adaptations to four weeks' resistance (RT) versus four weeks' endurance (END) training, and we investigated whether three single nucleotide polymorphisms (SNPs) were associated with these adaptations. METHODS: Thirty untrained, healthy, young men completed a cycling test to exhaustion to determine peak oxygen uptake (V̇O2peak), and a knee extension (KE) maximum voluntary isometric contraction (MVIC) of the right leg before and after four weeks' supervised RT (four sets of 10 repetitions at 80% single repetition maximum unilateral KE exercise, three times weekly) and four weeks' supervised END (30 min combined continuous/interval cycling, three times weekly), separated by a three-week washout phase. Participants were genotyped for the ACTN3 rs1815739, NOS3 rs2070744 and VEGFA rs2010963 SNPs. RESULTS: The intra-individual adaptations regarding percentage changes in MVIC force and V̇O2peak following RT and END, respectively, were unrelated (r2 = 0.003; P = 0.79). However, a VEGFA genotype × training modality interaction (P = 0.007) demonstrated that VEGFA GG homozygotes increased their MVIC force after RT (+ 20.9 ± 13.2%) more than they increased their V̇O2peak after END (+ 8.4 ± 9.1%, P = 0.005), and more than VEGFA C-allele carriers increased their MVIC force after RT (+ 12.2 ± 8.1%, P = 0.04). There were no genotype × training modality interactions for the ACTN3 or NOS3 SNPs. CONCLUSION: High/low responders to RT were not consequently high/low responders to END or vice versa. However, preferential adaptation of VEGFA rs2010963 GG homozygotes to RT over END, and their greater adaptation to RT compared to VEGFA C-allele carriers, indicate a novel genetic predisposition for superior RT adaptation.

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction.

Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction.

Impact of handgrip exercise and ischemic preconditioning on local and remote protection against endothelial reperfusion injury in young men.

Ischemic preconditioning (IPC), cyclical bouts of nonlethal ischemia, provides immediate protection against ischemic injury, which is evident both locally and remotely. Given the similarities in protective effects of exercise with ischemic preconditioning, we examined whether handgrip exercise also offers protection against endothelial ischemia-reperfusion (IR) injury and whether this protection is equally present in the local (exercised) and remote (contralateral, nonexercised) arm. Fifteen healthy males (age, 24 ± 3 yr; body mass index, 25 ± 2 kg/m2) attended the laboratory on three occasions. Bilateral brachial artery flow-mediated dilation (FMD) was examined at rest and after a temporary IR injury in the upper arm. Before the IR injury, in the dominant (local) arm, participants performed (randomized, counterbalanced): 1) 4 × 5 min unilateral handgrip exercise (50% maximal voluntary contraction), 2) 4 × 5 min unilateral IPC (220 mmHg), or 3) 4 × 5 min rest (control). Data were analyzed using repeated-measures general linear models. Allometrically scaled FMD declined after IR in the control condition (4.6 ± 1.3% to 2.2 ± 1.7%, P < 0.001), as well as following handgrip exercise (4.6 ± 1.6% to 3.4 ± 1.9%, P = 0.01), however, was significantly attenuated with IPC (4.5 ± 1.4% to 3.8 ± 3.5%, P = 0.14). There were no differences between the local and remote arm. Our findings reinforce the established protective effects of IPC in young, healthy males and also highlight a novel strategy to protect against IR injury with handgrip exercise, which warrants further study.

A systematic review summarizing local vascular characteristics of aneurysm wall to predict for progression and rupture risk of abdominal aortic aneurysms.

OBJECTIVE: At present, the rupture risk prediction of abdominal aortic aneurysms (AAAs) and, hence, the clinical decision making regarding the need for surgery, is determined by the AAA diameter and growth rate. However, these measures provide limited predictive information. In the present study, we have summarized the measures of local vascular characteristics of the aneurysm wall that, independently of AAA size, could predict for AAA progression and rupture. METHODS: We systematically searched PubMed and Web of Science up to September 13, 2021 to identify relevant studies investigating the relationship between local vascular characteristics of the aneurysm wall and AAA growth or rupture in humans. A quality assessment was performed using the ROBINS-I (risk of bias in nonrandomized studies of interventions) tool. All included studies were divided by four types of measures of arterial wall characteristics: metabolism, calcification, intraluminal thrombus, and compliance. RESULTS: A total of 20 studies were included. Metabolism of the aneurysm wall, especially when measured by ultra-small superparamagnetic iron oxide uptake, and calcification were significantly related to AAA growth. A higher intraluminal thrombus volume and thickness had correlated positively with the AAA growth in one study but in another study had correlated negatively. AAA compliance demonstrated no correlation with AAA growth and rupture. The aneurysmal wall characteristics showed no association with AAA rupture. However, the metabolism, measured via ultra-small superparamagnetic iron oxide uptake, but none of the other measures, showed a trend toward a relationship with AAA rupture, although the difference was not statistically significant. CONCLUSIONS: The current measures of aortic wall characteristics have the potential to predict for AAA growth, especially the measures of metabolism and calcification. Evidence regarding AAA rupture is scarce, and, although more work is needed, aortic wall metabolism could potentially be related to AAA rupture. This highlights the role of aortic wall characteristics in the progression of AAA but also has the potential to improve the prediction of AAA growth and rupture.

A positive neighborhood walkability is associated with a higher magnitude of leisure walking in adults upon COVID-19 restrictions: a longitudinal cohort study.

BACKGROUND: Previous cross-sectional and longitudinal observational studies revealed positive relationships between contextual built environment components and walking behavior. Due to severe restrictions during COVID-19 pandemic lockdowns, physical activity was primarily performed within the immediate living area. Using this unique opportunity, we evaluated whether built environment components were associated with the magnitude of change in walking activity in adults during COVID-19 restrictions. METHODS: Data on self-reported demographic characteristics and walking behaviour were extracted from the prospective longitudinal Lifelines Cohort Study in the Netherlands of participants ≥ 18 years. For our analyses, we made use of the data acquired between 2014-2017 (n = 100,285). A fifth of the participants completed the questionnaires during COVID-19 restrictive policies in July 2021 (n = 20,806). Seven spatial components were calculated for a 500m and 1650m Euclidean buffer per postal code area in GIS: population density, retail and service destination density, land use mix, street connectivity, green space density, sidewalk density, and public transport stops. Additionally, the walkability index (WI) of these seven components was calculated. Using multivariable linear regression analyses, we analyzed the association between the WI (and separate components) and the change in leisure walking minutes/week. Included demographic variables were age, gender, BMI, education, net income, occupation status, household composition and the season in which the questionnaire was filled in. RESULTS: The average leisure walking time strongly increased by 127 min/week upon COVID-19 restrictions. All seven spatial components of the WI were significantly associated with an increase in leisure walking time; a 10% higher score in the individual spatial component was associated with 5 to 8 more minutes of leisure walking/week. Green space density at the 500m Euclidean buffer and side-walk density at the 1650m Euclidean buffer were associated with the highest increase in leisure walking time/week. Subgroup analysis revealed that the built environment showed its strongest impact on leisure walking time in participants not engaging in leisure walking before the COVID-19 pandemic, compared to participants who already engaged in leisure walking before the COVID-19 pandemic. CONCLUSIONS: These results provide strong evidence that the built environment, corrected for individual-level characteristics, directly links to changes observed in leisure walking time during COVID-19 restrictions. Since this relation was strongest in those who did not engage in leisure walking before the COVID-19 pandemic, our results encourage new perspectives in health promotion and urban planning.

Impact of a comprehensive cardiac rehabilitation programme versus coronary revascularisation in patients with stable angina pectoris: study protocol for the PRO-FIT randomised controlled trial.

BACKGROUND: Currently, in the majority of patients with stable angina pectoris (SAP) treatment consists of optimal medical treatment, potentially followed by coronary angiography and subsequent coronary revascularisation if necessary". Recent work questioned the effectiveness of these invasive procedures in reducing re-events and improving prognosis. The potential of exercise-based cardiac rehabilitation on clinical outcomes in patients with coronary artery disease is well-known. However, in the modern era, no studies compared the effects of cardiac rehabilitation versus coronary revascularisation in patients with SAP. METHODS: In this multicentre randomised controlled trial, 216 patients with stable angina pectoris and residual anginal complaints under optimal medical treatment will be randomised to: 1) usual care (i.e., coronary revascularisation), or 2) a 12-month cardiac rehabilitation (CR) programme. CR consists of a multidisciplinary intervention, including education, exercise training, lifestyle coaching and a dietary intervention with a stepped decline in supervision. The primary outcome will be anginal complaints (Seattle Angina Questionnaire-7) following the 12-month intervention. Secondary outcomes include cost-effectiveness, ischemic threshold during exercise, cardiovascular events, exercise capacity, quality of life and psychosocial wellbeing. DISCUSSION: In this study, we will examine the hypothesis that multidisciplinary CR is at least equally effective in reducing anginal complaints as the contemporary invasive approach at 12-months follow-up for patients with SAP. If proven successful, this study will have significant impact on the treatment of patients with SAP as multidisciplinary CR is a less invasive and potentially less costly and better sustainable treatment than coronary revascularisations. TRIAL REGISTRATION: Netherlands Trial Register, NL9537. Registered 14 June 2021.

Rowing exercise increases cardiorespiratory fitness and brachial artery diameter but not traditional cardiometabolic risk factors in spinal cord-injured humans.

PURPOSE: This study assessed the effects of upper-body rowing exercise on cardiorespiratory fitness, traditional cardiometabolic risk factors, and vascular health in individuals with spinal cord injury (SCI). METHODS: Seventeen male and female adults with chronic (> 1 yr) motor-complete and incomplete SCI (level of injury: C4-L3) were randomized to control (CON, n = 9) or exercise (UBROW, n = 8). Participants in UBROW performed 12-week, 3 weekly sessions of 30-min upper-body ergometer rowing exercise, complying with current exercise guidelines for SCI. Cardiorespiratory fitness ([Formula: see text]O2peak), traditional risk factors (lipid profile, glycemic control) as well as inflammatory and vascular endothelium-derived biomarkers (derived from fasting blood samples) were measured before and after 6 (6W) and 12 weeks (12W). Brachial artery resting diameter and flow-mediated dilation (FMD) were determined by ultrasound as exploratory outcomes. RESULTS: UBROW increased [Formula: see text]O2peak from baseline (15.1 ± 5.1 mL/kg/min; mean ± SD) to 6W (16.5 ± 5.3; P < 0.01) and 12W (17.5 ± 6.1; P < 0.01). UBROW increased resting brachial artery diameter from baseline (4.80 ± 0.72 mm) to 12W (5.08 ± 0.91; P < 0.01), with no changes at 6W (4.96 ± 0.91), and no changes in CON. There were no significant time-by-group interactions in traditional cardiometabolic blood biomarkers, or in unadjusted or baseline diameter corrected FMD. Explorative analyses revealed inverse correlations between changes (∆12W-baseline) in endothelin-1 and changes in resting diameter (r = - 0.56) and FMD% (r = - 0.60), both P < 0.05. CONCLUSION: These results demonstrate that 12 weeks of upper-body rowing complying with current exercise guidelines for SCI improves cardiorespiratory fitness and increases resting brachial artery diameter. In contrast, the exercise intervention had no or only modest effects on traditional cardiometabolic risk factors. The study was registered at Clinicaltrials.gov (N-20190053, May 15, 2020).