HOWARD, BETHANY J.1,2; FRASER, STEVE F.2; SETHI, PARNEET1; CERIN, ESTER3; HAMILTON, MARC T.4; OWEN, NEVILLE1,5,6; DUNSTAN, DAVID W.1,2,5,6,7; KINGWELL, BRONWYN A.1
Sedentary behaviors—characterized by posture (sitting or reclining) and low levels of metabolic energy expenditure—occupy the major portion of adults’ waking hours, primarily through sitting at work, TV viewing, and other screen-based entertainment, and time spent sitting in cars (4). Several recent studies have reported detrimental associations of sedentary behaviors (most commonly TV viewing) with all-cause and cardiovascular mortality, even when accounting for leisure-time physical activity (32). Recent epidemiological evidence has suggested that adults whose sedentary time is mostly uninterrupted (prolonged unbroken sitting) have a poorer cardiometabolic health profile compared with those characterized as having more frequent interruptions or breaks in their sedentary time (9,10). This has been corroborated by experimental findings from our laboratory, indicating that the inclusion of regular light-intensity or moderate-intensity ambulatory breaks reduced postprandial glucose and insulin in sedentary overweight/obese adults to a similar extent, relative to uninterrupted sitting (5).
From the perspective of thrombotic risk, advocating interruptions in sitting time is not an entirely novel approach. In the 1950s, frequent breaks (getting up and moving around) in sitting time were recommended to reduce the risk of venous thrombosis (VT) (13,22). These recommendations were subsequently supported by evidence, indicating that frequent ambulatory breaks (2 min every 30 min) throughout a work day are sufficient to avoid the loss of plasma volume induced by uninterrupted sitting (35), yet the optimal intensity of the ambulation is unknown. It is possible that light-intensity activity would be sufficient to reduce the risk of VT because active foot movements have been reported to reduce sitting induced venous stasis (11,20). However, evidence is also required on the effects of breaking up sitting time with activity of varied intensity on the other two components of VT pathogenesis—hypercoagulation and endothelial dysfunction, and their possible interactions (15).
To better understand the mechanisms that may lead to the increased thrombotic risk of excessive sitting, it is necessary to control the relevant activity parameters: frequency, volume, type, and intensity of activity breaks. However, most studies have focused on the elevated risk of VT during air travel (25–27) and thereby have typically evaluated the effects of hypoxia (12,34,37) and not specifically the influence of reduced skeletal muscle contractile activity induced through sitting. It is also pertinent to study these mechanisms in an at risk population. Most previous studies that have investigated the effects of excessive sitting on hemostatic parameters have been limited to younger (<40 yr) healthy, nonobese populations (12,30,34,36). Examining responses among those at a greater risk of thrombotic events—specifically older and overweight obese populations—may provide greater insights into the mechanisms underlying the adverse hemostatic consequences of too much sitting.
In a randomized, crossover trial involving sedentary overweight older adults (45–65 yr), we examined the acute effects of a single period of uninterrupted sitting on hemostatic and hematological parameters compared with sitting interrupted by intermittent bouts of either light-intensity or moderate-intensity walking. We hypothesized that uninterrupted sitting would increase blood coagulation parameters and reduce blood volume and that brief intermittent bouts of either light- or moderate-intensity walking would attenuate such effects.
The descriptions of the participant characteristics and the screening and testing procedures for this study have been described in detail previously (5). Briefly, overweight or obese (body mass index [BMI] > 25 kg·m−2) adults (45–65 yr) were recruited from the general community between April 2009 and August 2010 into a randomized, three-period, three-treatment crossover trial involving a single bout of sitting with and without intermittent bouts of light- or moderate-intensity activity. Exclusion criteria consisted of employment in a nonsedentary occupation, low daily TV viewing (<2 h·d−1); regularly engaged in the recommended amount of physical activity (≥150 min·wk−1); BMI > 45 kg·m−2; current smoker; pregnant; non-English speaking; on anticoagulant, carbohydrate, or lipid-lowering medication; and clinically diagnosed with acute/chronic illness or known physical activity contraindications. The study was approved by the Alfred Hospital and Deakin University Human Ethics committees and was carried out in accordance with the Declaration of Helsinki. Participants provided signed, written informed consent. The study was registered as a clinical trial with the Australian New Zealand Clinical Trials Registry (ACTRN12609000656235).
Participants were provided with written and verbal instructions to refrain from moderate- to vigorous-intensity exercise, alcohol, and caffeine in the 48 h before each condition. During this time, physical activity and sedentary time was objectively measured using an ActiGraph GT1M accelerometer (ActiGraph, Pensacola, FL) in combination with activity and food diary records. A minimum washout period of 6 d was used between each condition to eliminate potential carryover effects.
Participants reported to the laboratory setting for each condition between 0700 and 0800 h after an overnight fast (≥8 h) to control for circadian variance. Body mass was assessed before the commencement of each trial day. In each of the three conditions, blood samples were collected via an indwelling venous catheter from the antecubital vein of the forearm at baseline (preintervention = −2 h) and on completion (postintervention = 5 h), 18 min after the last activity bout. Blood sampling was performed under strict aseptic conditions using standard operating procedures for the coagulation parameters measured. Before blood sampling, the catheter dead space was cleared and the sample discarded. Samples for the current study included 3 mL into an ethylenediaminetetraacetic acid (EDTA) vacutainer for the full blood examination, followed by another 3-mL sample into an EDTA vacutainer for measurement of von Willebrand factor (vWF) and D-dimer. Finally, a 2.7-mL sample was drawn into a citrate vacutainer for measurement of activated partial thromboplastin time (aPTT), prothrombin time (PT), and fibrinogen. The catheter was then flushed with 2 mL of saline. After initial blood collection, participants remained seated for 2 h before the consumption of a standardized test drink (time = 0 h), consisting of 75 g carbohydrate (100% corn maltodextrin powder; Natural Health, Australia) and 50 g fat (Calogen; Nutricia, Australia) to assess responses in a postprandial state (5). Throughout each condition, participants were permitted to consume water, with consumption kept constant across the trial. Under supervision, participants complied with the respective trial condition protocols for the remaining 5 h.
As described previously (5), each participant performed the three-trial conditions in a randomized order, determined via balanced blocks prepared for male and female participants.
1. Uninterrupted sitting—participants remained seated.
2. Sitting interrupted by light-intensity activity breaks—participants rose from the seated position every 20 min throughout the intervention period (time = 0–5 h) and completed a 2-min bout of light-intensity treadmill walking at 3.2 km·h−1. Upon completion of each bout, they returned to the seated position.
3. Sitting interrupted by moderate-intensity activity breaks—identical procedure to condition 2; however, the activity bouts were of a moderate intensity, corresponding with a treadmill speed between 5.8 and 6.4 km·h−1.
This was determined for each individual during the familiarization session (5) and entailed commencement of walking at 5.8 km·h−1 with 0.1 km·h−1 incremental increases every minute until the participant reported an RPE between 12 and 14. In all three conditions, participants were seated in a lounge chair and instructed to minimize excessive movement, only rising to void, except activity breaks. The pathology technicians and team statistician were blinded to the trial condition.
Plasma preparation and analytical methods.
Sodium citrate blood samples were analyzed by Alfred Pathology on the day of testing using an automated coagulation analyzer (DiagnosticaStago STA (R)) for aPTT, PT via international normalized ratio, and fibrinogen via the Clauss (2) method with their respective reagents: aPTT s (Trinity Biotech TriniCLOT), neoplastine C1 plus, and fibrinogen (5) reagent (DiagnosticaStago STA (R)). Hematocrit (Hct), hemoglobin (Hb), red blood cell count (RBC), white blood cell count (WBC), mean platelet volume (MPV), and platelet count (PC) were measured with a Beckman Coulter LH 785 analyzer using standard methods. The intra-assay coefficient of variation for these analyses ranged from 2% to 4.4%. Plasma volume was calculated using Dill and Costill’s (3) method.
EDTA blood samples were kept on ice and centrifuged for 15 min at 13,000 rpm at 4°C, and the plasma was removed and stored at −80°C. Stored samples were analyzed in duplicate on site (Baker IDI) via ELISA for vWF antigen (Imubind; American Diagnostica, Stamford, CT) and D-dimer (Technozym; Technolone, Vienna, Austria), with intra-assay coefficient of variations ≤10%. Plasma fibrinogen, vWF, D-dimer, and WBC were corrected for plasma volume.
Sample size selection was based on power calculations for the original primary outcome measures for the trial (glucose and insulin) to achieve a power of 0.90, while adopting a two-tailed 5% probability level (5). Generalized estimating equations (GEE models) with exchangeable working correlation matrix to account for the dependency in the data (repeated measures) were used to evaluate the differential effects of the trial conditions on the outcomes (21,28). The GEE models enabled the examination of between-condition differences in all variables and adjustment for potentially important covariates (age, sex, and body mass), baseline (−2 h) outcome values, and order effects (28). If more than five missing samples were present, GEE models were replaced with multilevel generalized latent and mixed models to ensure missing samples were not treated as missing completely at random (29). Carryover effects were not formally tested, given the minimum 6-d washout period between conditions and the fact that interventions were performed in a randomized order. A probability level of 0.05 was adopted. All statistical analyses were performed using Stata 12 for Windows (StataCorp LP). Data are reported as mean (95% confidence interval [CI]) in the text and table and as estimated marginal mean ± SEM in the figures.
All hemostatic parameters were available for the 19 participants. Data for Hct, Hb, RBC, WBC, PC, and MPV were missing for one participant in the moderate condition, with another participant missing data for PC in the uninterrupted sitting condition. For MPV, there was a total of nine missing data, with data unavailable in all conditions for two participants, and an additional two missing from the moderate condition and one from the light-intensity condition. Data were missing either due to unsuitable (sample clotting or outside of measurable range) or incomplete analysis. Where plasma volume correction was unavailable, the unadjusted values for all conditions and parameters were used.
Those included in the analyses were 19 participants (11 men and 8 women) who had fully completed all three conditions. For men, the mean ± SD age was 54.2 ± 5.6 yr, body mass was 99.5 ± 18.0 kg, and BMI was 32.4 ± 4.3 kg·m−2; for women, the mean age was 53.3 ± 3.5 yr, body mass was 79.2 ± 10.5 kg, and BMI was 29.5 ± 2.7 kg·m−2. Of the eight women, five were postmenopausal (two surgically induced), two were perimenopausal, and one was premenopausal. Of these women, one was taking hormone replacement therapy (estradiol gel) and none were taking oral contraceptives.
The unadjusted means at baseline and at the completion of each trial condition along with the adjusted (age, sex, body mass, baseline outcome values, and order effects) net differences (postintervention minus baseline) for each variable and condition are presented in Table 1. There were no differences at baseline between conditions for any of the parameters except WBC, which was 0.43 × 109 L−1 (95% CI = 0.02–0.85, P = 0.042) lower at baseline in the moderate-intensity activity condition compared with uninterrupted sitting but did not differ between the remaining conditions. As previously reported, there were no differences between trials for dietary and accelerometer-derived physical activity data before each of the respective conditions (5).
Plasma fibrinogen increased from baseline after consumption of the test drink with uninterrupted sitting and sitting interrupted with moderate-intensity activity, but not in the sitting interrupted with light-intensity activity condition (Table 1). After adjustment for potential confounders, the change in plasma fibrinogen was 0.17 g·L−1 (95% CI = 0.01–0.32, P < 0.05) less after sitting interrupted by light-intensity activity compared with uninterrupted sitting (Fig. 1). There were no significant differences between the remaining conditions for plasma fibrinogen.
PT decreased significantly in all three conditions from baseline, whereas aPTT decreased significantly in the sitting interrupted with moderate-intensity activity condition only (Table 1). vWF increased significantly in the sitting interrupted with moderate-intensity activity condition only. No significant changes were observed for D-dimer in any of the conditions. There were no significant between-condition net differences for PT, aPTT, vWF, or D-dimer.
Plasma volume decreased significantly across all three conditions (Table 1), to a lesser extent with the interrupted sitting conditions compared with uninterrupted sitting (Fig. 2). Hct, Hb, RBC, WBC, and PC increased significantly from baseline in all three conditions (Table 1). Compared with uninterrupted sitting, the net difference in Hct, Hb, and RBC was less in the two activity conditions, whereas WBC increased more in the sitting interrupted with moderate-intensity activity condition only (Fig. 2). MPV did not change with uninterrupted sitting or sitting with light-intensity activity but increased significantly after the sitting with moderate-intensity activity condition (Table 1) and was significantly higher in this condition relative to uninterrupted sitting (Fig. 2). There were no between-condition differences in PC.
These are the first findings on the hemostatic effects of interrupting sitting time with intermittent short walking breaks. In support of our hypothesis, activity breaks attenuated increases seen in plasma fibrinogen (light-intensity only), Hct, Hb, and RBC and the reduction in plasma volume with uninterrupted sitting in sedentary obese/overweight adults. In the context of VT and broader aspects of cardiometabolic health, this may be a potential beneficial outcome because these parameters—particularly fibrinogen—have been shown to be highly correlated with atherogenesis, thrombosis, and ischemia (16). In contrast, WBC and MPV were higher in the moderate-intensity condition compared with uninterrupted sitting, indicating a possible acute inflammatory effect of the higher intensity activity breaks.
Uninterrupted sitting is thought to increase thrombotic risk through multiple mechanisms, but predominantly via venous stasis (11). In the current study and earlier studies (12,36), this is characterized by increases in key blood viscosity parameters that influence blood flow including plasma fibrinogen, Hct, Hb, RBC, and reduced plasma volume (6). Our observation of an elevation in plasma fibrinogen (irrespective of correction for plasma volume changes) also supports the hypothesis for hypercoagulation because fibrinogen is integral to both primary and secondary clot formation (17). However, given there were no between-condition differences in the remaining hemostatic parameters, it is difficult to determine the relative role of venous stasis versus direct effects on coagulation signaling cascades. On the basis of previous research (25,30,31,34,36), it is probable that in the acute context, changes in blood volume that increase blood viscosity and decrease blood flow are more likely to underlie the increased risk of thrombosis associated with uninterrupted or excessive sitting.
In addition to the previously reported benefits of breaks in sitting time for glucose (5), we observed attenuations in blood volume parameters and (for the first time) plasma fibrinogen after sitting interrupted with light-intensity activity. Although the average difference in plasma fibrinogen for the light-intensity activity condition compared with uninterrupted sitting was small (0.17 g·L−1 or 6.5%), considerable variations were observed at the individual level with a 1.0-g·L−1 (39%) difference observed for one participant and ≥0.40 g·L−1 (17%–38%) for a further seven participants. The magnitude of such changes observed with light-intensity activity breaks in these individuals exceeds the 10%–15% reduction in fibrinogen reported after longer-term pharmaceutical intervention with certain fibrate drugs (18) and may therefore have potential relevance for disease states. However, to reach such conclusions, future investigations will need to demonstrate that these findings persist over accumulated bouts across several days.
It is possible that with a larger sample size, a significant difference in fibrinogen for moderate-intensity may have also been observed. However, it is also possible that the higher intensity of the moderate-activity condition may have induced an acute inflammatory response including fibrinogen release as part of the acute-phase reaction (19). The higher WBC and MPV in the moderate condition relative to uninterrupted sitting are consistent with this possibility (1).
Findings from acute exercise studies may be of relevance to interpreting the current findings. For instance, 5- to 20-fold increases in WBC and fibrinogen (23) and greater MPV (33) have been reported after high-intensity exercise and are consistent with an acute inflammatory response (1). However, chronic exercise training can lead to a reduction in these parameters (7). Therefore, despite moderate-intensity activity interruptions in sitting time not appearing to be as beneficial as light-intensity activity interruptions in the acute context, if accumulated across consecutive days, it is possible that a reduction may be observed. Irrespective of the findings for moderate-intensity activity, from a practical perspective, the changes observed in the light-intensity activity condition may provide a feasible and acceptable approach to reducing and interrupting overall sitting time.
A major strength of the current study is the strict monitoring of the activity parameters within a rigorously controlled laboratory setting, allowing for the comparison of the effects of uninterrupted sitting with interrupted sitting. In addition, we were able to assess the integrated effects of uninterrupted sitting and the test meal, an important consideration because the postprandial state predominates during waking hours. In previous studies that have assessed postprandial hemostatic responses to various macronutrient composition meals, fibrinogen has not been altered (8,14,24,37). However, most if not all studies that have evaluated postprandial states have not controlled for physical activity. As such, it is not possible to reach conclusions about whether the meal provided in the current study amplified the response to uninterrupted sitting or had no effect.
There are some limitations to our study. First, we examined only an acute exposure to uninterrupted sitting in a single day with interruptions of a fixed frequency and duration, with two different activity-break intensities. To better understand implications for long-term cardiovascular risk, it will be important to understand the changes induced in hemostatic risk factors after repeated long-term exposure to sitting, as well as the dose–response relationships associated with different frequencies, durations, and/or intensities of activity-break conditions. In addition, the interpretation of the current findings is limited to sedentary middle age overweight/obese adults who are at greater hemostatic risk than younger, active, nonobese individuals. The sample size and heterogeneity with regard to menopausal status did not allow an assessment of gender differences in responses. Testing was not standardized for menstrual cycle stage in the peri- and premenopausal women. It will be important to study larger and more heterogeneous populations so that the influence of factors such as age, sex, fitness, and body composition can also be examined. In addition, investigating the responses in individuals with clinically impaired vascular or hemostatic functioning (e.g., patients with diabetes or patients with peripheral or coronary artery disease) may provide further insights.
In summary, compared with uninterrupted sitting, we observed less increase in plasma fibrinogen and blood volume parameters (Hct, Hb, and RBC) that influence blood viscosity and less reduction in plasma volume with the introduction of intermittent activity (walking) bouts during sitting. These findings suggest that in the acute setting, changes in both fibrinogen and blood viscosity may contribute to the well-documented increased risk of thrombosis associated with excessive sitting. However, future research using larger sample sizes and a more extended exposure should be directed at elucidating potential mechanisms, in addition to determining the optimal timing, intensity, and type of activity undertaken to interrupt sitting time. Assuming that these findings can be replicated, they further support the case that reducing and frequently breaking up sedentary time may have important health benefits.
The authors are grateful to Dr. Zane Kaplan and Jason Gardner for their input and consultation regarding the contents of this manuscript, Miriam Clayfield and Robyn Larsen for their supervision of the study, and the participants for making this study possible.
This work was supported by the National Health and Medical Research Council (NHMRC) (project grant no. 540107, program grant nos. 569940 and 1000900), a scholarship from Deakin University School of Exercise and Nutrition Sciences to BJH, an NHMRC senior principal research fellowship to NO (no. 1003960), a Victorian Public Health Research Fellowship and an ARC Future Research Fellowship to DWD (no. FT100100918), an NHMRC principal research fellowship to BAK (no. 526604), and by the Victorian Government’s Operational Infrastructure Support Program.
The authors declare no conflict of interest.
The funders of this study had no role in the trial, and the results do not constitute endorsement by the American College of Sports Medicine.
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