Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Decreased cerebrovascular blood flow and function are associated with lower cognitive functioning and increased risk of neurodegenerative diseases. Prolonged sitting impairs peripheral blood flow and function, but its effects on the cerebrovasculature are unknown. This study explored the effect of uninterrupted sitting and breaking up sitting time on cerebrovascular blood flow and function of healthy desk workers. Fifteen participants (10 male, 35.8 ± 10.2 yr, body mass index: 25.5 ± 3.2 kg/m) completed, on separate days, three 4-h conditions in a randomized order: 1) uninterrupted sitting (SIT), 2) sitting with 2-min light-intensity walking breaks every 30 min (2WALK), or 3) sitting with 8-min light-intensity walking breaks every 2 h (8WALK). At baseline and 4 h, middle cerebral artery blood flow velocity (MCAv) and CO reactivity (CVR) of the MCA and carotid artery were measured using transcranial Doppler (TCD) and duplex ultrasound, respectively. Cerebral autoregulation (CA) was assessed with TCD using a squat-stand protocol and analyzed to generate values of gain and phase in the very low, low, and high frequencies. There was a significant decline in SIT MCAv (-3.2 ± 1.2 cm/s) compared with 2WALK (0.6 ± 1.5 cm/s, P = 0.02) but not between SIT and 8WALK (-1.2 ± 1.0 cm/s, P = 0.14). For CA, the change in 2WALK very low frequency phase (4.47 ± 4.07 degrees) was significantly greater than SIT (-3.38 ± 2.82 degrees, P = 0.02). There was no significant change in MCA or carotid artery CVR ( P > 0.05). Results indicate that prolonged uninterrupted sitting in healthy desk workers reduces cerebral blood flow; however, this is offset when frequent short-duration walking breaks are incorporated. NEW & NOTEWORTHY Prolonged uninterrupted sitting in healthy desk workers reduces cerebral blood flow. However, this reduction in cerebral blood flow is offset when frequent short-duration walking breaks are incorporated into this sitting period. For those who engage in long periods of sedentary behavior, chronically breaking up these sitting periods with frequent active break strategies may have important implications for cerebrovascular health; however, further research should explore this hypothesis.

Sedentary behavior has a strong association with cardiovascular disease (CVD) risk, which may be independent of physical activity. To date, the mechanism(s) that mediate this relationship are poorly understood. We hypothesize that sedentary behavior modifies key hemodynamic, inflammatory, and metabolic processes resulting in impaired arterial health. Subsequently, these vascular impairments directly and indirectly contribute to the development of CVD.

Breaking up prolonged sitting with physical activity (PA) breaks prevents conduit artery dysfunction. However, the optimal break strategy to achieve this, in terms of the frequency or duration of PA, is not known. This study assessed the effect of breaking up sitting with different PA break strategies on lower limb peripheral artery endothelial function. Fifteen participants (10 male, 35.8 ± 10.2 years, BMI: 25.5 ± 3.2 kg m −2 ) completed, on separate days, three 4‐h conditions in a randomized order: (1) uninterrupted sitting (SIT), (2) sitting with 2‐min light‐intensity walking breaks every 30 min (2WALK), or (3) sitting with 8‐min light‐intensity walking breaks every 2 h (8WALK). At baseline and 4 h, superficial femoral artery function (flow‐mediated dilation; FMD), blood flow, and shear rate (SR) were assessed using Doppler ultrasound. For each condition, the change in outcome variables was calculated and data were statistically analyzed using a linear mixed model. There was no significant main effect for the change in FMD ( P = 0.564). A significant main effect was observed for the change in blood flow ( P = 0.022), with post hoc analysis revealing a greater reduction during SIT (−42.7 ± 14.2 mL·min) compared to 8WALK (0.45 ± 17.7 mL·min; P = 0.012). There were no significant main effects for mean, antegrade, or retrograde SR ( P > 0.05). Superficial femoral artery blood flow, but not FMD, was reduced following uninterrupted sitting. This decline in blood flow was prevented with longer duration, less frequent walking breaks rather than shorter, more frequent breaks suggesting the dose (duration and frequency) of PA may influence the prevention of sitting‐induced decreases in blood flow.