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Effect of Prolonged Sitting and Breaks in Sitting Time on Endothelial Function

THOSAR, SAURABH S.1; BIELKO, SYLVANNA L.1; MATHER, KIEREN J.2; JOHNSTON, JEANNE D.1; WALLACE, JANET P.1

Medicine & Science in Sports & Exercise: April 2015 - Volume 47 - Issue 4 - p 843–849
doi: 10.1249/MSS.0000000000000479
APPLIED SCIENCES

Sitting time (ST) is associated with cardiovascular disease risk factors, whereas breaking ST has been reported to be beneficial for reducing cardiovascular risk.

Purpose The objective of this study is to examine the effects of breaking ST on superficial femoral artery (SFA) endothelial function.

Hypotheses 1) Prolonged sitting would induce endothelial dysfunction and changes in shear forces, and 2) breaking ST with brief periods of activity would prevent attenuation in endothelial function.

Methods Twelve nonobese men (24.2 ± 4.2 yr) participated in two randomized 3-h sitting trials. In the sitting (SIT) trial, subjects were seated on a firmly cushioned chair for 3 h without moving their lower extremities. In the breaking ST trial (ACT), subjects sat similar to the SIT trial but walked on a treadmill for 5 min at 2 mph at 30 min, 1 h 30 min, and 2 h 30 min during the sitting interval. SFA flow-mediated dilation (FMD) was assessed at baseline, 1 h, 2 h, and 3 h in each trial. Statistical analyses were performed using dependent variables SFA FMD and shear rates. Significance was set at P ≤ 0.05.

Results In the SIT trial, there was a significant decline in SFA FMD from baseline to 3 h (baseline, 4.72% ± 3.78%; 1 h, 0.52% ± 0.85%; 2 h, 1.66% ± 1.11%; 3 h, 2.2% ± 2.15; P < 0.05 by ANOVA) accompanied by a decline in mean shear rate and antegrade shear rate but no difference in shear rate (area under the curve). By two-way repeated-measures ANOVA, ACT prevented the sitting-induced decline in FMD (baseline, 4.5% ± 2.3%; 1 h, 5.04% ± 2.85%; 2 h, 5.28% ± 5.05%; 3 h, 6.9% ± 4.5%) along with no decline in shear rates.

Conclusion Three hours of sitting resulted in a significant impairment in shear rate and SFA FMD. When light activity breaks were introduced hourly during sitting, the decline in FMD was prevented.

1Department of Kinesiology, Indiana University School of Public Health, Indiana University Bloomington, IN; 2Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

Address for correspondence: Saurabh S. Thosar, Ph.D., Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, L606/RJH1553A, Portland, OR 97239; E-mail: thosar@ohsu.edu.

Submitted for publication March 2014.

Accepted for publication August 2014.

Prolonged sitting is a common (8) but deleterious (1) behavior in contemporary humans. Increased sitting time (ST) has been associated with chronic diseases and increased risk of mortality even while controlling for leisure time physical activity (1). Epidemiological evidence also suggests that ST is directly associated with the biomarkers of cardiovascular diseases (CVD) such as total cholesterol, LDL cholesterol, triglycerides, waist circumference, and blood pressure (6,25). In contrast, breaking ST has been associated with beneficial patterns of CVD risk markers including lower waist circumference, triglycerides, and 2-h plasma glucose (9). In the limited literature examining the beneficial physiological effects of breaking ST, Dunstan et al. (4) reported that breaking ST via low-intensity and moderate-intensity activity attenuated the rise in postprandial glucose and insulin, which was observed after a test meal in an acute bout of 7 h of sitting. Similarly, Stephens et al. (32) observed a 39% reduction in insulin action in a daylong sitting condition as compared with the active condition. Furthermore, Duvivier et al. (5) found breaking ST was beneficial for plasma lipids and insulin sensitivity even more than adding 1 h of vigorous-intensity physical exercise for 4 d.

In the past three decades, impaired endothelial function has emerged as a predictor of CVD risk (3), and in some studies, it is shown to be at least as predictive as traditional risk factors (37). In fact, endothelial function is impaired even before the traditional risk factors are expressed (7). The effects of prolonged sitting on the endothelial function and the potential beneficial effects of breaking ST have not been previously published. We have proposed that prolonged sitting may lead to a shear-mediated endothelial dysfunction (35). The purpose of this study was to investigate the effects of 3 h of sitting on lower extremity mean shear rate (MSR) and endothelial function and to study whether breaking ST modulated these effects. We hypothesized that 3 h of sitting would lead to a decline in MSR and a decline in superficial femoral artery (SFA) endothelial function as measured by flow-mediated dilation (FMD). A second hypothesis was that systematic low-intensity physical activity (5 min at 2 mph) used to break this ST would mitigate the decline in endothelial function.

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METHODS

Study design

This study consisted of two screening visits and two sitting trials in random sequence, one with uninterrupted sitting (SIT) and one with breaks in ST (ACT). FMD measurements were conducted at baseline, 1 h, 2 h, and 3 h in both the trials. All procedures for the study were approved by Indiana University Institutional Review Board, and participants gave written informed consent for their participation (Fig. 1).

FIGURE 1

FIGURE 1

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Subjects

To be included, subjects had to self-report that they were nonsmokers and not taking any antihypertensive, lipid-lowering, and/or antidiabetic medications. To be included, they needed to have total cholesterol ≤240 mg·dL−1 and triglycerides ≤200 mg·dL−1. We recruited individuals who performed <150 min·wk−1 of moderate-intensity physical activity or <75 min·wk−1 of vigorous-intensity physical activity. We intentionally chose a group of subjects who do not meet the physical activity guidelines recommended by the Centers for Disease Control and Prevention (2). Subjects were asked to maintain their regular diet patterns throughout the study duration and to discontinue any over-the-counter antioxidant supplement at least 7 d before the first session. On the basis of our pilot data, for the primary dependent variable SFA FMD, we estimated that 12 subjects would be needed to find a significant difference between trials with a statistical power of >0.80 at α ≤ 0.05.

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Screening visits

At the first visit, all experimental procedures were explained to the subjects and they were familiarized with the laboratory setting. After obtaining a written informed consent, height, weight, and blood pressure were measured using standard procedures, and a medical health history and habits questionnaire (12) was completed to screen for any preexisting medical conditions and to determine physical activity. Blood pressure was measured during an additional screening visit, at the same time of day, to confirm previous measurements.

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Testing trials

Subjects arrived at the laboratory after an overnight fast of at least 6 h between 0700 and 0900 h. The arrival time was matched for both trials within each subject. Subjects were also asked to refrain from any caffeinated drink for at least 8 h before reporting to the laboratory. Upon their arrival in the laboratory, all subjects self-reported adhering to the fasting schedule. During both trials, the subjects remained seated for 3 h without moving their legs (perpendicular to the ground) or feet (resting on the floor). Subjects were seated for ∼5–10 min before the first measurement. Subjects were allowed to move their arms, not vigorously, for example, to use a computer or do light reading during the nontesting periods of the trials. Arm movement was not quantified. The FMD and other vascular function parameters were measured at baseline, 1 h, 2 h, and 3 h. The two trials were performed in random order, separated by a minimum of 2 d and a maximum of 7 d. The SIT trial was uninterrupted sitting for 3 h, whereas in the ACT trial subjects completed three 5-min bouts of walking at 2 mph on an adjacent treadmill at 30 min, 1 h 30 min, and 2 h 30 min during the sitting interval.

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SFA FMD

Endothelial function was measured using SFA FMD in accordance with current guidelines (34). We chose SFA for two reasons: 1) It is a readily accessible artery for measuring FMD in a sitting position. 2) SFA FMD has been shown to be largely nitric oxide dependent (15). Each measurement was performed in a dark, quiet, and climate-controlled room (22°C–25°C). A 5-cm × 84-cm automatic blood pressure cuff (E-20 rapid cuff inflator; D.E. Hokanson, Bellevue, WA) was placed on their right thigh about 7 cm above the knee joint, distal to the SFA recording location. Images of the SFA were obtained longitudinally 7–10 cm below the inguinal line with a 2-D high-resolution ultrasound system (Terason t3000; Teratech Corp., Burlington, MA), using a 5- to 12-MHz multifrequency linear-array transducer. Once satisfactory images of near and far arterial walls were obtained, the transducer was secured and stabilized in a stereotactic clamp, and landmarks were made on the subject’s skin to ensure similar placement of the transducer for subsequent FMD procedures and shear rate assessments within and between conditions. Subjects were encouraged to keep the landmarks between the two trials. In addition to imaging the arterial dimensions, Doppler ultrasound was used to concurrently measure SFA blood velocity. Doppler flow signals were corrected at an insonation angle of 60°, and the sample volume was placed in the middle of the artery.

Diameter images and Doppler measurements of blood velocity were continuously recorded for 45 s at baseline before cuff inflation. The automatic blood pressure cuff was then rapidly inflated to 250 mm Hg and maintained for 5 min until cuff deflation. Diameter and blood velocity recording resumed before cuff deflation and continued for 5 min after deflation. Ultrasound images were continuously recorded at five frames per second with Camtasia (TechSmith, Okemos, MI) and stored as .avi files (12,21). This procedure was repeated hourly across the sitting intervals.

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Arterial diameters and blood velocities

Off-line analysis of diameters was performed using automated edge-detection software (Brachial Analyzer; Medical Imaging Applications LLC, Coralville, IA) as previously described (21). This software allows the technician to determine a region of interest where the near and far vessel walls are most clear. The vessel wall borders are then detected using an optimal graph search-based segmentation that uses a combination of pixel density and image gradient as an objective function. All analyzed images were reviewed by the technician and edited when needed to ensure that diameter measures were always determined from the intima–lumen interface at the near and far vessel wall. Blood velocities were determined using custom-made software that we developed for this project by selecting a region of interest that surrounded the Doppler wave. The velocity–time integral was used to calculate the mean blood velocity for each cardiac cycle. Diameters and blood velocities were not ECG gated (14,26). The peak dilation after cuff deflation was determined using the highest 3-s moving average and was presented as a percentage change from baseline diameter (FMD%). SFA shear rate was used as an estimate of arterial shear stress and was calculated for each FMD% at baseline and during the postocclusion period using the following formula: 4V m D −1, where V m is the mean blood velocity (cm·s−1) and D is the mean arterial diameter (cm). All measurements and analyses were performed by a single researcher (ST) who was blinded to the participant identity and treatment condition for each image file.

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Statistical analysis

Descriptive analysis was performed to summarize subject characteristics. Within both trials, one-way ANOVA was conducted with the baseline diameter as the dependent variable. Within the SIT trial, one-way ANOVA was conducted with the following dependent variables: baseline diameter, FMD%, and shear rates (antegrade shear rate (ASR), MSR, retrograde shear rate, peak shear rate, and shear rate (area under the curve) (SRauc)). When an effect was found, pairwise comparisons were used to locate significant differences across time. The observed effect size was reported for ANOVA interactions and main effects as partial eta squared (η 2). Comparisons across the two treatment conditions for FMD were performed using a 2-way repeated-measures ANOVA, evaluating whether the effect of sitting differed between conditions; again, pairwise comparisons were used to identify significant differences at each time point if the main effects were positive. All values are expressed as the mean ± SE of the mean, and the alpha level for statistical significance was set a priori at 0.05. All statistical calculations were performed using IBM SPSS Statistics 21.0 software (IBM SPSS Inc., Chicago, IL).

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RESULTS

We recruited and tested 12 subjects who comprised a homogenous group of apparently healthy inactive young men (Table 1). We were unable to collect data for one time-point FMD on one subject in the ACT trial, and this subject’s data were excluded from the two-way ANOVA between trials.

TABLE 1

TABLE 1

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SIT trial

SFA baseline diameters are presented in Table 2. There was no significant difference between the baseline diameters from baseline to 3 h (η 2 = 0.112, P = 0.263).

TABLE 2

TABLE 2

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SFA FMD

There was a significant reduction in FMD across time in SIT each hour, from baseline to 3 h (η 2 = 0.481, P ≤ 0.001). The FMD was significantly reduced at 1, 2, and 3 h compared with baseline. There was no significant difference from baseline to 3 h in retrograde shear rate, peak shear rate, and SRauc (P > 0.05) (Fig. 2).

FIGURE 2

FIGURE 2

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Baseline ASR

There was a significant decline in the ASR from baseline to 3 h (η 2 = 0.209, P = 0.049). The ASR was significantly lower at 1 and 2 h compared with baseline.

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MSR

There was a significant decline in MSR from baseline across time (η 2 = 0.237, P = 0.028). MSR was significantly lower at 1 and 2 h as compared with baseline. Shear rate data are presented in Table 2.

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SIT and ACT trials

A 2 × 4 (trial × time) repeated-measures ANOVA was performed for the dependent variable FMD in the SIT and ACT trials. There was a significant trial–time interaction (P < 0.05) between FMD and time across trials. The variable of interest was the FMD difference between trials at each measurement (baseline, 1 h, 2 h, and 3 h). FMD between the two trials was not significantly different at baseline. However, FMD was significantly reduced in the SIT trial compared with the ACT trial at 1, 2, and 3 h (Fig. 2).

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DISCUSSION

The purpose of this study was to examine the effects of prolonged sitting and breaking ST on SFA endothelial function (FMD). We hypothesized that 3 h of sitting would lead to a decline in MSR and a decline in SFA endothelial function as measured by FMD. Our second hypothesis was that systematic low-intensity physical activity (5 min at 2 mph) would prevent the decline in FMD. Indeed, we discovered a decline in MSR during 3 h of sitting. We also discovered a significant attenuation of SFA FMD on 3 h of sitting. We also observed that when breaks with modest activity were added during the ST, the decline in FMD was not observed. This is the first study to our knowledge to examine the direct effects of prolonged sitting and breaking ST on endothelial function. There are numerous sitting opportunities in today’s society, including but not limited to sitting at work and sitting during transportation, and this area is of major public health concern. Our observations are the first experimental evidence of the effects of prolonged sitting on human vasculature and are important from a public health perspective.

Very little data have been published evaluating the effects of prolonged sitting on FMD on lower extremity vascular function. Padilla et al. (22) used a similar protocol to study the effects of hydrostatic load on popliteal artery FMD during 3 h of sitting and reported no significant difference in the FMD in the popliteal artery after 3 h of sitting. Our FMD results contradict the primary findings from this study. An important difference in study design may explain these contradictory results: Padilla moved the subjects from the sitting position to the prone position to measure the endothelial function, thereby breaking the static circumstance in the leg. This active postural change may have compromised their ability to observed adverse effects on FMD, as even a simple change in position involves muscle contractions and changes in flow patterns (20). We maintained the sitting stimulus during FMD measurement and found a significant decline in SFA FMD.

On the other hand, our MSR results are similar to those reported by Padilla et al. (22). We had expected that the mean baseline shear rate would decline over the 3 h of prolonged sitting (secondary to low blood flow in the legs [30]) and would be maintained during breaking ST. Our MSRs during the 3 h of sitting significantly declined from baseline by hour 1 and stayed low all through the 3 h of sitting. Padilla observed a significant decline in MSRs after just 30 min of sitting, which was maintained during 3 h of sitting. Their baseline measurement was, however, in the prone position. All our measurements were all in the seated position with the first measurement taken after ∼10 to 15 min of acclimatization. Thus, our findings are more robust because our design involves repeated measurements of FMD in one position. Our results suggest that sitting creates a milieu of low MSR and also leads to the decline in FMD. It is important to note that the hyperemic stimulus SRauc and retrograde shear did not change throughout the sitting trial. This implies that there was an impairment of endothelial function independent of any change in the hyperemic stimulus or retrograde shear. Another interesting finding from our study is the progressive decline in antegrade shear. Antegrade shear represents forward flow through the (superficial femoral) artery. Even in the absence of overt atherosclerosis, a chronic decrease in antegrade shear creates a proatherogenic milieu (36,40). Hence, we can hypothesize that repeated bouts of prolonged sitting may contribute to vascular aging, at least in the lower extremities. To summarize our results from the SIT trial, 3 h of uninterrupted sitting leads to a progressive decline in antegrade and MSR and the corresponding impairment in endothelial function.

We had hypothesized that breaks in ST (ACT trial) would prevent the decline in shear rates and FMD observed during the SIT trial. We found a significant difference in FMD between the SIT and ACT trials at 1, 2, and 3 h, with no significant difference observed at baseline. However, we did not find a significant difference in the MSR between these trials. Our subjects performed light-intensity physical activity 30 min, 1 h 30 min, and 2 h 30 min during the sitting interval, and we measured flow at 1, 2, and 3 h. Even this very light-intensity physical activity prevented the decline in FMD that was seen in the SIT trial and may explain the protective effect against sitting-induced impairment in FMD. Our MSR observations between trials are not different perhaps because of the timing of measurement. There was a lag of ∼25 min between the activity and the shear rate measurement. It is possible that the flow ephemerally increased on walking and had decreased closed to baseline attenuated at the time of measurement.

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Mechanisms

There are at least three possible mechanisms explaining the attenuation in FMD during sitting and its mitigation after breaking ST. These mechanisms may act separately or may be integrated.

First, in the seated position, the shear rates are lower than that in supine position (20). Once sitting commences, these shear rates initially decline and are maintained creating a condition of low flow in the lower extremity (22) (also seen in our measurements). Conditions of low flow have been associated with impaired endothelial function (19). In our study, we found a decline in SFA FMD during 3 h of sitting, which was associated with concurrent reductions in shear forces. Although no prior evidence exists that directly demonstrates the effects of exercise on shear in the SFA, it is logical that the low-intensity activity in our study episodically increased shear rate in the SFA (and other leg vessels). The brief intervals of low-level activity in our ACT trial appear to have been sufficient to prevent sitting-related reductions in shear.

A second possible mechanism can be blood viscosity. Viscosity has been shown to be higher in the legs after 2 h of sitting (11). Increased viscosity has been associated with increased coagulation and inflammatory markers (18), which in turn have been strongly associated with impaired endothelial function (39). Low shear rates are associated with clumping of red blood cells and increased viscosity (17). Conversely, increased shear rates from walking (ACT) (33) would intermittently oppose the rise in viscosity and coagulation markers, resulting in preserved FMD.

A third possibility is an increased muscle sympathetic nerve activity (MSNA). MSNA is higher during the upright sitting posture (13) and along with increased blood pressure (30) may result in a decline in FMD (10). Indeed, increased MSNA is also linked to increased proatherogenic shear patterns in the conduit arteries (23). Walking-induced muscular contractions would help in venous return thereby not requiring the sympathetic outflow compensation during prolonged sitting (24). In addition, light-intensity activity has been known to directly decrease MSNA (29). In our study, the light-intensity walking may have ephemerally lowered the MSNA and preserved shear patterns and FMD.

The burden of atherosclerotic lesions in the human peripheral vasculature is greater in the lower extremities than the upper extremities (16,28,31). Sitting is a common activity in today’s society. On the basis of our data in addition to the previous work on the adverse effects of sitting (20,22), we can hypothesize that perhaps repeated bouts of prolonged sitting result in chronic low shear rates in the lower extremities, which impair endothelial function and accelerate the atherosclerotic process in the lower extremity. Because the upper extremity is constantly mobile for activities of daily living, even during the seated position, upper extremity endothelial function may be relatively protected from the harmful effects of sitting.

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Limitations

Potential limitations of this study should be considered. We did not directly measure blood pressure or MSNA (13) in the lower extremity in the seated position. Padilla et al. (22) found that leg blood pressure was significantly higher during 3 h of sitting than at baseline. Blood pressure may be one of the mechanisms contributing to the decline in FMD (27). We considered measuring blood pressure; however, the occlusion of the cuff may have resulted in changes in the shear rates. The seated posture is known to increase MSNA (13). However, MSNA measurement would have compromised the strict nonmovement of the legs and thereby our study design. We did not measure viscosity. Because viscosity is an integral component of shear stress, viscosity measurement would have provided us with actual shear stress results without using shear rate as a surrogate measure for shear stress. However, viscosity measurement would have been relevant only if the blood was sampled from the legs. We attempted repeated blood draws from the lower extremities but were unsuccessful. Finally, absence of blood biomarkers sampled from the lower extremity is a clear limitation because we cannot relate locally sampled factors to a low shear-related mechanism and declining SFA FMD during sitting. As noted earlier, before the beginning of data collection, we attempted to master the technique to perform repeated blood draws via a vein in the leg, but we were unsuccessful. Indeed, we collected venous blood samples from the antecubital vein and analyzed the plasma for oxidative stress biomarkers. However, these biomarkers did not change during 3 h of sitting as compared with baseline similar to the brachial artery FMD implying that the local lower extremity effect could not be detected using the upper extremity measurements (38). Finally, during the measurement of FMD, most of our subjects did not have any dilation of the SFA at least at one measurement point. Only four subjects had nonzero FMD%. It is hence difficult to calculate and interpret SRauc, which is considered to be the stimulus for the dilation, and interpret the FMD normalized to SRauc. It is possible that the change in the FMD% was a direct result of the change in SRauc. However, on the basis of the available data, we cannot speculate this as a possible mechanism.

Despite these limitations, our study adds significant new information to the field of inactivity physiology. This is the first experimental evidence of the effects of prolonged sitting on human vasculature, performed using a robust protocol with all measurements taken in the seated position.

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CONCLUSIONS

SFA FMD exhibits an acute decline during 3 h of sitting. Starting at 1 h, FMD in the SFA attenuates and remains significantly low through 3 h of quiet sitting. This is complimentary to the significant decline in mean and ASR. The decline in FMD is counteracted by adding 5 min of light-intensity physical activity (2 mph) bouts each hour during the ST. Three hours of sitting is a common phenomenon in different settings such as the workplace, transportation, and leisure settings. Our results provide with first experimental evidence demonstrating that breaking ST protects endothelial function and hence may be antiatherosclerotic in nature. We believe our observations further the argument to have structured public health guidelines on limiting ST.

The authors thank Samantha Mayhew and Chad Wiggins for their assistance during data collection.

This project was funded in part through the American College of Sports Medicine Foundation’s doctoral student research grant and the Indiana University School of Public Health and Indiana University Graduate School’s grant-in-aid awarded to SST.

The authors report no conflict of interest.

The results do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

SEDENTARY ACTIVITY; FLOW-MEDIATED DILATION; INTERMITTENT ACTIVITY; LOW SHEAR RATE

© 2015 American College of Sports Medicine