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ObjectiveTo examine the effects of autoregulated (AUTO) and non-autoregulated (NAUTO) blood flow restriction (BFR) application on adverse effects, performance, cardiovascular and perceptual responses during resistance exercise.MethodsFifty-six healthy participants underwent AUTO and NAUTO BFR resistance exercise in a randomised crossover design using a training session with fixed amount of repetitions and a training session until volitional failure. Cardiovascular parameters, rate of perceived effort (RPE), rate of perceived discomfort (RPD) and number of repetitions were investigated after training, while the presence of delayed onset muscle soreness (DOMS) was verified 24 hours post-session. Adverse events during or following training were also monitored.ResultsAUTO outperformed NAUTO in the failure protocol (p<0.001), while AUTO scored significantly lower for DOMS 24 hours after exercise (p<0.001). Perceptions of effort and discomfort were significantly higher in NAUTO compared with AUTO in both fixed (RPE: p=0.014, RPD: p<0.001) and failure protocol (RPE: p=0.028, RPD: p<0.001). Sixteen adverse events (7.14%) were recorded, with a sevenfold incidence in the fixed protocol for NAUTO compared with AUTO (NAUTO: n=7 vs AUTO: n=1) and five (NAUTO) vs three (AUTO) adverse events in the failure protocol. No significant differences in cardiovascular parameters were found comparing both pressure applications.ConclusionAutoregulation appears to enhance safety and performance in both fixed and failure BFR-training protocols. AUTO BFR training did not seem to affect cardiovascular stress differently, but was associated with lower DOMS, perceived effort and discomfort compared with NAUTO.Trial registration number NCT04996680.

Total sleep deprivation (TSD) alters local cold tolerance and could thus increase the risk of cold injury. We evaluated the impact of acute caffeine intake, the main countermeasure to TSD‐related deleterious effects, on local cold tolerance before and after TSD. Thirty‐six healthy subjects underwent two TSD protocols (i.e., continuous wakefulness), with randomized crossover intake of acute caffeine or placebo (2.5 mg/kg) administered twice during wakefulness. Before and after 33 h of TSD, finger (index and annular) temperature and skin blood flow were assessed during cold‐water immersion (CWI, 5°C, 20 min) followed by 20 min of rewarming in ambient air. We showed no significant effects of TSD on mean finger temperature during CWI in the placebo condition, but a significant reduction of the minimal temperature (8.86°C ± 0.35°C vs. 8.64°C ± 0.27°C, p = 0.02). During rewarming, we showed a reduction in temperature in the placebo condition (p = 0.02 for the mean temperature and p = 0.03 for the maximal) and an increase in the skin blood flow disparity between fingers at the four points of laser speckle rewarming measurements (p = 0.03). After TSD, acute caffeine intake (vs. placebo) increased mean (+2.11°C ± 0.21°C, p = 0.01) and minimal (+0.61°C ± 0.10°C, p = 0.02) finger temperatures during CWI, and improved rewarming after CWI (mean and maximal temperatures) (+2.28°C ± 0.08°C, p = 0.01, and +2.06°C ± 0.12°C, p = 0.02, respectively). Before TSD, acute caffeine intake significantly increased (vs. placebo) mean temperatures during CWI (p = 0.03) and reduced pain from the onset (p = 0.03) to the end of CWI (p = 0.02) and the first 2 min of rewarming (p = 0.04). There was also a significant main effect of habitual daily caffeine consumption on minimal finger temperatures during CWI, which decreased significantly between 0 and 600 mg consumption (R2 = −0.43, p = 0.01), independently of the effects of day (before and after TSD) and treatment (caffeine and placebo conditions). These findings suggest that acute caffeine intake could be a protective countermeasure to local cold tolerance, particularly during TSD. However, habitual daily caffeine consumption is a factor of individual variability that should be recorded during CWI protocols. Clinical trial NCT03859882. What is the central question of this study? What is the effect of acute caffeine intake on local (finger) cold tolerance before and after total sleep deprivation (TSD)? What is the main finding and its importance? We found that acute caffeine intake (compared with placebo): (1) increased TSD‐related reductions in finger temperature and skin blood flow during rewarming after cold‐water immersion (CWI); and (2) decreased pain during CWI before TSD only. We also evidenced a significant effect of habitual daily caffeine consumption on minimal temperatures during CWI, without an interaction with TSD or acute caffeine intake.

Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4–24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis. Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.

Human brain functional networks contain a few densely connected hubs that play a vital role in transferring information across regions during resting and task states. However, the relationship of these functional hubs to measures of brain physiology, such as regional cerebral blood flow (rCBF), remains incompletely understood. Here, we used functional MRI data of blood-oxygenation-level–dependent and arterial-spin–labeling perfusion contrasts to investigate the relationship between functional connectivity strength (FCS) and rCBF during resting and an N -back working-memory task. During resting state, functional brain hubs with higher FCS were identified, primarily in the default-mode, insula, and visual regions. The FCS showed a striking spatial correlation with rCBF, and the correlation was stronger in the default-mode network (DMN; including medial frontal-parietal cortices) and executive control network (ECN; including lateral frontal-parietal cortices) compared with visual and sensorimotor networks. Moreover, the relationship was connection–distance dependent; i.e., rCBF correlated stronger with long-range hubs than short-range ones. It is notable that several DMN and ECN regions exhibited higher rCBF per unit connectivity strength (rCBF/FCS ratio); whereas, this index was lower in posterior visual areas. During the working-memory experiment, both FCS–rCBF coupling and rCBF/FCS ratio were modulated by task load in the ECN and/or DMN regions. Finally, task-induced changes of FCS and rCBF in the lateral-parietal lobe positively correlated with behavioral performance. Together, our results indicate a tight coupling between blood supply and brain functional topology during rest and its modulation in response to task demands, which may shed light on the physiological basis of human brain functional connectome.

The incidence of hypertension and cardiovascular disease (CVD) correlates with latitude and rises in winter. The molecular basis for this remains obscure. As nitric oxide (NO) metabolites are abundant in human skin, we hypothesized that exposure to UVA may mobilize NO bioactivity into the circulation to exert beneficial cardiovascular effects independently of vitamin D. In 24 healthy volunteers, irradiation of the skin with two standard erythemal doses of UVA lowered blood pressure (BP), with concomitant decreases in circulating nitrate and rises in nitrite concentrations. Unexpectedly, acute dietary intervention aimed at modulating systemic nitrate availability had no effect on UV-induced hemodynamic changes, indicating that cardiovascular effects were not mediated via direct utilization of circulating nitrate. UVA irradiation of the forearm caused increased blood flow independently of NO synthase (NOS) activity, suggesting involvement of pre-formed cutaneous NO stores. Confocal fluorescence microscopy studies of human skin pre-labeled with the NO-imaging probe diaminofluorescein 2 diacetate revealed that UVA-induced NO release occurs in a NOS-independent, dose-dependent manner, with the majority of the light-sensitive NO pool in the upper epidermis. Collectively, our data provide mechanistic insights into an important function of the skin in modulating systemic NO bioavailability, which may account for the latitudinal and seasonal variations of BP and CVD.

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T‐type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L‐ and T‐type calcium channel blocker (CCB)) or nifedipine (L‐type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium‐dependent vasodilator) and sodium nitroprusside (endothelium‐independent vasodilator) both with and without co‐infusion of N‐acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra‐arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co‐infusion of NAC did not affect endothelium‐dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks’ inhibition of T‐ and L‐type calcium channels augments endothelium‐dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T‐type calcium channel inhibition can counteract endothelial dysfunction. What is the central question of this study? Does T‐type calcium channel inhibition prevent age‐related endothelium dysfunction in humans? What is the main finding and its importance? Eight weeks of L+T‐type calcium channel blockade (CCB) increased endothelium‐dependent vasodilatation in the leg of otherwise healthy elderly males, while 8 weeks of L‐type CCB only did not. Thus, T‐type calcium channels may be involved in endothelium dysfunction.

Abstract Rationale Exposure to combustion-derived air pollution is associated with an early (1–2 h) and sustained (24 h) rise in cardiovascular morbidity and mortality. We have previously demonstrated that inhalation of diesel exhaust causes an immediate (within 2 h) impairment of vascular and endothelial function in humans. Objectives To investigate the vascular and systemic effects of diesel exhaust in humans 24 hours after inhalation. Methods Fifteen healthy men were exposed to diesel exhaust (particulate concentration, 300 μg/m3) or filtered air for 1 hour in a double-blind, randomized, crossover study. Twenty-four hours after exposure, bilateral forearm blood flow, and inflammatory and fibrinolytic markers were measured before and during unilateral intrabrachial bradykinin (100–1,000 pmol/min), acetylcholine (5–20 μg/min), sodium nitroprusside (2–8 μg/min), and verapamil (10–100 μg/min) infusions. Measurements and Main Results Resting forearm blood flow, blood pressure, and basal fibrinolytic markers were similar 24 hours after either exposure. Diesel exhaust increased plasma cytokine concentrations (tumor necrosis factor-α and interleukin-6, p < 0.05 for both) but appeared to reduce acetylcholine (p = 0.01), and bradykinin (p = 0.08) induced forearm vasodilatation. In contrast, there were no differences in either endothelium-independent (sodium nitroprusside and verapamil) vasodilatation or bradykinin-induced acute plasma tissue plasminogen activator release. Conclusions Twenty-four hours after diesel exposure, there is a selective and persistent impairment of endothelium-dependent vasodilatation that occurs in the presence of mild systemic inflammation. These findings suggest that combustion-derived air pollution may have important systemic and adverse vascular effects for at least 24 hours after exposure.

Young individuals with post‐traumatic stress disorder (PTSD) display peripheral vascular and autonomic nervous system dysfunction, two factors potentially stemming from a redox imbalance. It is currently unclear if these aforementioned factors, observed at rest, alter peripheral haemodynamic responses to exercise in this population. This study examined haemodynamic responses to handgrip exercise in young individuals with PTSD following acute antioxidant (AO) supplementation. Thirteen young individuals with PTSD (age 23 ± 3 years), and 13 age‐ and sex‐matched controls (CTRL) participated in the study. Exercise‐induced changes to arm blood flow (BF), mean arterial pressure (MAP) and vascular conductance (VC) were evaluated across two workloads of rhythmic handgrip exercise (3 and 6 kg). The PTSD group participated in two visits, consuming either a placebo (PL) or AO prior to their visits. The PTSD group demonstrated significantly lower VC (P = 0.04) across all exercise workloads (vs. CTRL), which was significantly improved following AO supplementation. In the PTSD group, AO supplementation improved VC in participants possessing the lowest VC responses to handgrip exercise, with AO supplementation significantly improving VC responses (3 and 6 kg: P < 0.01) by blunting elevated exercise‐induced MAP responses (3 kg: P = 0.01; 6 kg: P < 0.01). Lower VC responses during handgrip exercise were improved following AO supplementation in young individuals with PTSD. AO supplementation was associated with a blunting of exercise‐induced MAP responses in individuals with PTSD displaying elevated MAP responses. This study revealed that young individuals with PTSD exhibit abnormal, peripherally mediated exercise responses that may be linked to a redox imbalance. What is the central question of this study? Do young individuals with post‐traumatic stress disorder (PTSD) display abnormal peripheral haemodynamic responses during exercise? What is the main finding and its importance? Young individuals with PTSD displayed lower vascular conductance (VC) during handgrip exercise compared to healthy counterparts. Antioxidant supplementation notably improved VC responses, especially in the subset of PTSD participants with the highest pressor responses during exercise. This study underscores abnormal peripherally mediated exercise responses in young individuals with PTSD, suggesting a potential link to a redox imbalance.

IntroductionThe application of blood flow restriction (BFR) to low-intensity exercise may be able to increase strength not only in the trained limb but also in the homologous untrained limb. Whether this effect is repeatable and how that change compares to that observed with higher intensity exercise is unknown.PurposeExamine whether low-intensity training with BFR enhances the cross-education of strength compared to exercise without BFR and maximal efforts.MethodsA total of 179 participants completed the 6-week study, with 135 individuals performing isometric handgrip training over 18 sessions. Participants were randomly assigned to one of four groups: 1) low-intensity (4 × 2 min of 30% MVC; LI, n = 47), 2) low-intensity with blood flow restriction (LI + 50% arterial occlusion pressure; LI-BFR, n = 41), 3) maximal effort (4 × 5 s of 100% MVC; MAX, n = 47), and 4) non-exercise control (CON, n = 44).ResultsLI-BFR was the only group that observed a cross-education in strength (CON: 0.64 SD 2.9 kg, LI: 0.95 SD 3.6 kg, BFR-LI: 2.7 SD 3.3 kg, MAX: 0.80 SD 3.1 kg). In the trained hand, MAX observed the greatest change in strength (4.8 SD 3.3 kg) followed by LI-BFR (2.8 SD 4.0 kg). LI was not different from CON. Muscle thickness did not change in the untrained arm, but ulna muscle thickness was increased within the trained arm of the LI-BFR group (0.06 SD 0.11 cm).ConclusionIncorporating BFR into low-intensity isometric training led to a cross-education effect on strength that was greater than all other groups (including high-intensity training).

PurposeThis study aimed to investigate the impact of short-term low energy availability (LEA) on vascular function in young, regularly menstruating women.MethodsParticipants were 19 women, aged 22.9 ± 4.2 years, with body mass index 18–30 kg·m2. They were divided into two groups and completed two conditions in a crossover design: a 3-day control condition (CON) with an energy availability of 45 kcals·kgFFM−1·day−1 and a 3-day LEA condition of 15 kcals·kgFFM−1 day–1. Assessments were conducted during the early follicular phase of the menstrual cycle. Outcome measures included forearm blood flow (FBF), heart rate, blood pressure, arterial stiffness, resting energy expenditure (REE), metabolic blood markers and body composition.ResultsSignificant time-by-condition interactions were found for resting FBF (p = .004), REE (p = .042), triiodothyronine (p = .006), β-hydroxybutyrate (p = .002) and body mass (p < .001). Resting FBF was 1.43 ± 1.01 and 1.31 ± 0.61 (arbitrary units) at pre and post, respectively, in LEA and 1.52 ± 0.7 and 1.76 ± 0.57 at pre and post in CON. The LEA condition led to a decrease in triiodothyronine (pre: 1.54 ± 0.28, post: 1.29 ± 0.27 ng ml−1), REE (pre: 1588 ± 165, post: 1487 ± 160 kcals day−1) and body mass (pre: 61.4 ± 7.5, post: 59.6 ± 7.3 kg). Changes in resting FBF were significantly correlated with changes in REE in the LEA condition (r = 0.53; p = 0.02).ConclusionShort-term LEA modifies regional blood flow and this might contribute to the observed decreased in REE. Findings emphasize the need for careful management of energy availability in populations at risk of LEA.