Retrograde shear rate (SR) in the brachial artery (BA) is associated with endothelial dysfunction; a precursor to atherosclerosis. The BA does not typically manifest clinical atherosclerosis, whereas the superficial femoral artery (SFA) is more prone to developing plaque. Examine whether the impact of incremental levels of retrograde SR differs between atherosclerosis‐prone (i.e., SFA) and ‐resistant vessels (i.e., BA) in healthy men. Thirteen healthy young men reported three times to the laboratory. We examined BA flow‐mediated dilation (FMD) before and after 30‐min exposure to cuff inflation around the forearm at 0, 30, and 60 mmHg, to manipulate retrograde SR. Subsequently, the 30‐min intervention was repeated in the SFA, using the same cuff pressure as in the forearm. Order of testing (vessel and intervention) was randomized among subjects. We found a dose‐dependent increase in retrograde SR with 30 and 60 mmHg cuff inflation, which was present in both the BA and SFA (all P < 0.05). BA and SFA FMD decreased after the 30‐min intervention (“time”: P = 0.012), and this was dependent on cuff pressure (“cuff × time”: P = 0.024). A significant decrease in FMD was observed after 60 mmHg only and this change was similarly present in both arteries (“time × artery”: P = 0.227). Moreover, the BA and SFA demonstrate a similar relationship between changes in retrograde SR and FMD (r = 0.498 and 0.475, respectively). Our study demonstrates that acute exposure to an increase in retrograde shear leads to comparable decreases in FMD in atherosclerotic‐prone and ‐resistant conduit arteries in humans.

The objectives of our study were to examine 1) the proportion of responders and nonresponders to exercise training in terms of vascular function; 2) a priori factors related to exercise training-induced changes in conduit artery function, and 3) the contribution of traditional cardiovascular risk factors to exercise-induced changes in artery function. We pooled data from our laboratories involving 182 subjects who underwent supervised, large-muscle group, endurance-type exercise training interventions with pre-/posttraining measures of flow-mediated dilation (FMD%) to assess artery function. All studies adopted an identical FMD protocol (5-min ischemia, distal cuff inflation), contemporary echo-Doppler methodology, and observer-independent automated analysis. Linear regression analysis was used to identify factors contributing to changes in FMD%. We found that cardiopulmonary fitness improved, and weight, body mass index (BMI), cholesterol, and mean arterial pressure (MAP) decreased after training, while FMD% increased in 76% of subjects (P < 0.001). Training-induced increase in FMD% was predicted by lower body weight (β = -0.212), lower baseline FMD% (β = -0.469), lower training frequency (β = -0.256), and longer training duration (β = 0.367) (combined: P < 0.001, r = 0.63). With the exception of a modest correlation with total cholesterol (r = -0.243, P < 0.01), changes in traditional cardiovascular risk factors were not significantly related to changes in FMD% (P > 0.05). In conclusion, we found that, while some subjects do not demonstrate increases following exercise training, improvement in FMD% is present in those with lower pretraining body weight and endothelial function. Moreover, exercise training-induced change in FMD% did not correlate with changes in traditional cardiovascular risk factors, indicating that some cardioprotective effects of exercise training are independent of improvement in risk factors.

Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness.

Reperfusion is mandatory after ischemia but also triggers ischemia-reperfusion (I/R) injury. Ischemic preconditioning (IPC) can limit endothelial I/R injury. Nonetheless, translation of IPC to the clinical arena is often disappointing. Since application of IPC typically relates to older patients, efficacy of IPC may be attenuated with aging. Our objective was to examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to I/R injury. We included 15 healthy young (20-25 yr) and 15 older (68-77 yr) men. We examined brachial artery endothelial function using flow-mediated dilation (FMD) before and after arm I/R (induced by inflation of an upper-arm blood pressure cuff for 20 min and 15 min of reperfusion). In a randomized order, I/R was preceded by IPC or a control intervention consisting of three cycles of 5 min upper-arm cuff inflation to 220 or 20 mmHg, respectively. As a result, in young men, FMD decreased significantly after I/R (6.4 ± 2.7 to 4.4 ± 2.5%). This decrease was not present when I/R was preceded by IPC (5.9 ± 2.3 to 5.6 ± 2.5%). IPC-induced protection appeared to be significantly reduced in the elderly patients (P = 0.04). Although FMD decreased after I/R in older men (3.5 ± 1.7 to 2.5 ± 1.0%), IPC could not prevent this (3.7 ± 2.1 to 2.2 ± 1.1%). In conclusion, this study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after I/R in the brachial artery. This provides a possible explanation for the problematic translation of strategies that reduce I/R injury from preclinical work to the clinical arena.

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endothelial and smooth muscle function using flow-mediated dilation (FMD) and glyceryl trinitrate (GTN) administration in 13 type 2 diabetes patients (59±6 years) and 10 healthy subjects (58±7 years) before, during (2-weekly) and after an 8-week training program.Arterial structure was assessed via peak blood flow and artery diameter. RESULTS Training increased peak oxygen uptake (P=0.03), comparable between groups (P=0.276). We observed a similar impact of training on brachial artery vasomotor function across the training period in diabetes patients and controls (FMD/GTN-ratio), with a higher FMD/GTN-ratio at 2, 6 and 8 weeks (P=0.036). Artery diameter, peak blood flow or peak diameter had not changed after training. CONCLUSION Training leads to rapid improvement in brachial artery vascular function in diabetes patients and controls. In contrast to previous observations in healthy young subjects, the increase in function was preserved after 8 weeks of training in middleaged diabetes patients and controls, suggesting a different time-course in vascular adaptations in subjects with endothelial dysfunction.

Endothelial ischemia-reperfusion (I/R) injury importantly contributes to the poor prognosis during ischemic (myocardial) events. Preconditioning, i.e., repeated exposure to short periods of ischemia, effectively reduces endothelial I/R injury. In the present study, we examined the hypothesis that exercise has preconditioning effects on endothelial I/R injury. Therefore, we studied whether an acute bout of endurance or interval exercise is able to protect against endothelial I/R injury. In 17 healthy young subjects, we examined changes in brachial artery endothelial function using flow-mediated dilation (FMD) before and after a bout of high-intensity interval exercise, moderate-intensity endurance exercise, or a control intervention. Subsequently, I/R injury was induced by inflation of a blood pressure cuff around the upper arm to 220 mmHg for 20 min and 20 min of reperfusion followed by another FMD measurement. Near-infrared spectrometry was used to examine local tissue oxygenation during exercise. No differences in brachial artery FMD were found at baseline for the three conditions. I/R induced a significant decline in FMD (7.1±2.3 to 4.3±2.3, P<0.001). When preceded by the interval exercise bout, no change in FMD was present after I/R (7.7±3.1 to 7.2±3.1, P=0.56), whereas the decrease in FMD after I/R could not be prevented by the endurance exercise bout (7.8±3.1 to 3.8±1.7, P<0.001). In conclusion, a single bout of lower limb interval exercise, but not moderate-intensity endurance exercise, effectively prevents brachial artery endothelial I/R injury. This indicates the presence of a remote preconditioning effect of exercise, which is selectively present after short-term interval but not continuous exercise in healthy young subjects.

BackgroundAlthough acute elevation in retrograde shear rate (SR) impairs endothelial function, no previous study has explored the effect of prolonged elevation of retrograde SR on conduit artery vascular function. We examined the effect of 2‐weeks elevation of retrograde SR on brachial artery endothelial function in young and in older men.Methods and ResultsThirteen healthy young (23±2 years) and 13 older men (61±5 years) were instructed to continuously wear a compression sleeve around the right forearm to chronically (2 weeks) elevate brachial artery retrograde SR in 1 arm. We assessed SR, diameter, and flow‐mediated dilation in both the sleeve and contralateral control arms at baseline and after 30 minutes and 2 weeks of continuous sleeve application. The sleeve intervention increased retrograde SR after 30 minutes and 2 weeks in both young and older men (P=0.03 and 0.001, respectively). In young men, brachial artery flow‐mediated dilation % was lower after 30 minutes and 2 weeks (P=0.004), while resting artery diameter was reduced after 2 weeks (P=0.005). The contralateral arm showed no change in retrograde SR or flow‐mediated dilation % (P=0.32 and 0.26, respectively), but a decrease in diameter (P=0.035). In older men, flow‐mediated dilation % and diameter did not change in either arm (all P>0.05).ConclusionsThirty‐minute elevation in retrograde SR in young men caused impaired endothelial function, while 2‐week exposure to elevated levels of retrograde SR was associated with a comparable decrease in endothelial function. Interestingly, these vascular changes were not present in older men, suggesting age‐related vascular changes to elevation in retrograde SR.