Tim H. A. Schreuder

Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans.

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.

Acute impact of retrograde shear rate on brachial and superficial femoral artery flow‐mediated dilation in humans

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.

Exercise training and artery function in humans: nonresponse and its relationship to cardiovascular risk factors

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.

The impact of obesity on physiological responses during prolonged exercise

Background:Prolonged, moderate-intensity exercise training is routinely prescribed to subjects with obesity. In the general population, this type of exercise can lead to fluid and sodium imbalance. However, little is known whether obesity alters the risk of fluid and sodium imbalances.Objective:This study examined physiological responses, such as core body temperature, fluid and sodium balance, in lean (BMI<25), overweight (25<BMI<30) and obese (BMI>30) subjects during prolonged moderate-intensity exercise.Subjects:A total of 93 volunteers (24–80 years), stratified for BMI, participated in the Nijmegen Marches and walked 30–50 km at a self-selected pace. Heart rate and core body temperature were recorded every 5 km. Subjects reported fluid intake, while urine output was measured and sweat rate was calculated. Baseline and post-exercise plasma sodium levels were determined, and urinary specific gravity levels were assessed before and after exercise.Results:BMI groups did not differ in training status preceding the experiment. Exercise duration (8 h 41±1 h 36 min) and intensity (72±9% HRmax) were comparable across groups, whereas obese subjects tended to have a higher maximum core body temperature than lean controls (P=0.06). Obese subjects demonstrated a significantly higher fluid intake (P<0.001) and sweat rate (P<0.001), but lower urine output (P<0.05) compared with lean subjects. In addition, higher urine specific gravity levels were observed in obese versus lean subjects after exercise (P<0.05). Furthermore, plasma-sodium concentration did not change in lean subjects after exercise, whereas plasma-sodium levels increased significantly (P<0.001) in overweight and obese subjects. Also, overweight and obese subjects demonstrated a significantly larger decrease in body mass after exercise than lean controls (P<0.05).Conclusion:Obese subjects demonstrate a larger deviation in markers of fluid and sodium balance than their lean counterparts during prolonged moderate-intensity exercise. These findings suggest that overweight and obese subjects, especially under strenuous environmental conditions, have an increased risk to develop fluid and sodium imbalances.

Impact of 2‐Weeks Continuous Increase in Retrograde Shear Stress on Brachial Artery Vasomotor Function in Young and Older Men

Background Although 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 Results Thirteen 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). Conclusions Thirty‐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.

Breath acetone to monitor life style interventions in field conditions: An exploratory study

To assess whether breath acetone concentration can be used to monitor the effects of a prolonged physical activity on whole body lipolysis and hepatic ketogenesis in field conditions.

Elevation in blood flow and shear rate prevents hyperglycemia-induced endothelial dysfunction in healthy subjects and those with type 2 diabetes

Hyperglycemia, commonly present after a meal, causes transient impairment in endothelial function. We examined whether increases in blood flow (BF) protect against the hyperglycemia-mediated decrease in endothelial function in healthy subjects and patients with type 2 diabetes mellitus (T2DM). Ten healthy subjects and 10 age- and sex-matched patients with T2DM underwent simultaneous bilateral assessment of brachial artery endothelial function by means of flow-mediated dilation (FMD) using high-resolution echo-Doppler. FMD was examined before and 60, 120, and 150 min after a 75-g oral glucose challenge. We unilaterally manipulated BF by heating one arm between minute 30 and minute 60. Oral glucose administration caused a statistically significant, transient increase in blood glucose in both groups (P < 0.001). Forearm skin temperature, brachial artery BF, and shear rate significantly increased in the heated arm (P < 0.001), and to a greater extent compared with the nonheated arm in both groups (interaction effect P < 0.001). The glucose load caused a transient decrease in FMD% (P < 0.05), whereas heating significantly prevented the decline (interaction effect P < 0.01). Also, when correcting for changes in diameter and shear rate, we found that the hyperglycemia-induced decrease in FMD can be prevented by local heating (P < 0.05). These effects on FMD were observed in both groups. Our data indicate that nonmetabolically driven elevation in BF and shear rate can similarly prevent the hyperglycemia-induced decline in conduit artery endothelial function in healthy volunteers and in patients with type 2 diabetes. Additional research is warranted to confirm that other interventions that increase BF and shear rate equally protect the endothelium when challenged by hyperglycemia.

Impact of endothelin blockade on acute exercise‐induced changes in blood flow and endothelial function in type 2 diabetes mellitus

What is the central question of this study? Doesendothelin receptor blockade increase exercise‐induced blood flow and post‐exercise endothelial function in men with type 2 diabetes? What is the main finding and its importance? Despite increasing exercise‐induced blood flow, endothelin receptor blockade did not impact post‐exercise endothelial function. The increase in blood flow may have beneficial effects in repeated exercise training.

Impact of hypoxic versus normoxic training on physical fitness and vasculature in diabetes.

BACKGROUND Exercise training improves physical fitness, insulin resistance, and endothelial function in type 2 diabetes. Hypoxia may further optimize these beneficial effects. The aim of this study was to compare the effects of hypoxic versus normoxic exercise training on physical fitness, endothelial function, and insulin resistance in type 2 diabetes. METHODS Peak oxygen consumption, flow mediated dilation (endothelial function), and glucose homeostasis were assessed in 19 patients (55±7 years) before and after an 8-week intervention. Subjects were randomly allocated to normoxic (21% O2, n=9) or hypoxic (16.5% O2, n=10) exercise training. Endothelium-independent dilation was examined using sublingual administration of glyceryl trinitrate, and used to calculate the ratio between endothelium-dependent and -independent dilation. RESULTS Exercise training improved physical fitness and brachial artery ratio between endothelium-dependent and -independent dilation (both p<0.05), whilst these exercise training-induced changes were similar in both groups (interaction-effects p>0.05). Exercise training did not significantly change brachial artery flow-mediated dilation or glyceryl trinitrate-response, superficial femoral artery flow-mediated dilation, or glucose homeostasis, whilst hypoxia did not alter the impact of exercise training. CONCLUSION Contrary to our hypothesis, hypoxia does not potentiate the effect of exercise training on physical fitness, vascular function, or glucose homeostasis in type 2 diabetes.

Effect of black tea consumption on brachial artery flow-mediated dilation and ischaemia–reperfusion in humans

Tea consumption is associated with reduced cardiovascular risk. Previous studies found that tea flavonoids work through direct effects on the vasculature, leading to dose-dependent improvements in endothelial function. Cardioprotective effects of regular tea consumption may relate to the prevention of endothelial ischaemia-reperfusion (IR) injury. Therefore, we examined the effect of black tea consumption on endothelial function and the ability of tea to prevent IR injury. In a randomized, crossover study, 20 healthy subjects underwent 7 days of tea consumption (3 cups per day) or abstinence from tea. We examined brachial artery (BA) endothelial function via flow-mediated dilation (FMD), using high resolution echo-Doppler, before and 90 min after tea or hot water consumption. Subsequently, we followed a 20-min ischaemia and 20-min reperfusion protocol of the BA after which we measured FMD to examine the potential of tea consumption to protect against IR injury. Tea consumption resulted in an immediate increase in FMD% (pre-consumption: 5.8 ± 2.5; post-consumption: 7.2 ± 3.2; p < 0.01), whilst no such change occurred after ingestion of hot water. The IR protocol resulted in a significant decrease in FMD (p < 0.005), which was also present after tea consumption (p < 0.001). This decline was accompanied by an increase in the post-IR baseline diameter. In conclusion, these data indicate that tea ingestion improves BA FMD. However, the impact of the IR protocol on FMD was not influenced by tea consumption. Therefore, the cardioprotective association of tea ingestion relates to a direct effect of tea on the endothelium in humans in vivo.