Saurabh S. Thosar

Effect of prolonged sitting and breaks in sitting time on endothelial function.

UNLABELLED 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.

Sitting and endothelial dysfunction: The role of shear stress

Summary Sedentary activity is a modifiable life-style behavior and a key component in the etiology of atherosclerotic cardiovascular disease (ACVD). US adults and children spend more than half their waking time in sedentary pursuits. Sedentary activity has been shown to result in impaired insulin sensitivity, impaired metabolic function and attenuated endothelial function, which are classic markers of ACVD. Sedentary activity is defined as ‘sitting without otherwise being active.’ This behavior promotes reduced muscular activity of the lower extremities which decreases leg blood flow, increases blood pooling in the calf, augments mean arterial pressure, and deforms arterial segments resulting in low mean shear stress (SS). SS activates distinct physiological mechanisms which have been proposed to be protective against ACVD; specifically through a SS-induced endothelium-derived nitric oxide mechanism. Reduced bioavailability of nitric oxide creates a pro-oxidant milieu resulting in increased oxidative stress. There is sufficient evidence which demonstrates that endothelial function is attenuated in the presence of oxidative stress. Sedentary activity results in low SS in the lower extremities which may result in increased oxidative stress and impaired endothelial function. This review furthers the use of sitting as model to study the effects of inactivity, discusses possible physiological mechanisms and suggests future directions.

Implementation of Sleep and Circadian Science: Recommendations from the Sleep Research Society and National Institutes of Health Workshop.

Sairam Parthasarathy, MD1; Mary A. Carskadon, PhD2,3; Girardin Jean-Louis, PhD4; Judith Owens, MD, MPH5; Adam Bramoweth, PhD6; Daniel Combs, MD1; Lauren Hale, PhD7; Elizabeth Harrison, PhD8; Chantelle N. Hart, PhD9; Brant P. Hasler, PhD10; Sarah M. Honaker, PhD, CBSM11; Elisabeth Hertenstein, PhD12; Samuel Kuna, MD13; Clete Kushida, MD, PhD14; Jessica C. Levenson, PhD10; Caitlin Murray, MA15; Allan I. Pack, MD, PhD13; Vivek Pillai, PhD16; Kristi Pruiksma, PhD17; Azizi Seixas, PhD4; Patrick Strollo, MD18; Saurabh S. Thosar, PhD19; Natasha Williams, MD4; Daniel Buysse, MD6

Antioxidant Vitamin C Prevents Decline in Endothelial Function during Sitting

Background This study was designed to test the hypothesis that antioxidant Vitamin C prevents the impairment of endothelial function during prolonged sitting. Material/Methods Eleven men (24.2±4.4 yrs) participated in 2 randomized 3-h sitting trials. In the sitting without vitamin C (SIT) and the sitting with vitamin C (VIT) trial, participants were seated for 3 h without moving their legs. Additionally, in the VIT trial, participants ingested 2 vitamin C tablets (1 g and 500 mg) at 30 min and 1 h 30 min, respectively. Superficial femoral artery (SFA) flow-mediated dilation (FMD) was measured hourly for 3 h. Results By a 1-way ANOVA, there was a significant decline in FMD during 3 h of SIT (p<0.001). Simultaneously, there was a significant decline in antegrade (p=0.04) and mean (0.037) shear rates. For the SIT and VIT trials by a 2-way (trial × time) repeated measures ANOVA, there was a significant interaction (p=0.001). Pairwise testing revealed significant between-SFA FMD in the SIT and VIT trial at each hour after baseline, showing that VIT prevented the decline in FMD 1 h (p=0.009), 2 h (p=0.016), and 3 h (p=0.004). There was no difference in the shear rates between SIT and VIT trials (p>0.05). Conclusions Three hours of sitting resulted in impaired SFA FMD. Antioxidant Vitamin C prevented the decline in SFA FMD, suggesting that oxidative stress may contribute to the impairment in endothelial function during sitting.

Role of the circadian system in cardiovascular disease

All species organize behaviors to optimally match daily changes in the environment, leading to pronounced activity/rest cycles that track the light/dark cycle. Endogenous, approximately 24-hour circadian rhythms in the brain, autonomic nervous system, heart, and vasculature prepare the cardiovascular system for optimal function during these anticipated behavioral cycles. Cardiovascular circadian rhythms, however, may be a double-edged sword. The normal amplified responses in the morning may aid the transition from sleep to activity, but such exaggerated responses are potentially perilous in individuals susceptible to adverse cardiovascular events. Indeed, the occurrence of stroke, myocardial infarction, and sudden cardiac death all have daily patterns, striking most frequently in the morning. Furthermore, chronic disruptions of the circadian clock, as with night-shift work, contribute to increased cardiovascular risk. Here we highlight the importance of the circadian system to normal cardiovascular function and to cardiovascular disease, and identify opportunities for optimizing timing of medications in cardiovascular disease.

Morning impairment in vascular function is unrelated to overnight sleep or the inactivity that accompanies sleep.

Adverse cardiovascular events, such as myocardial infarction and sudden cardiac death, occur more frequently in the morning. Prior studies have shown that vascular endothelial function (VEF), a marker of cardiovascular disease, is attenuated during physical inactivity and declines across the night. We sought to determine whether a morning attenuation in VEF is a result of prior sleep or the inactivity that inevitably accompanies sleep. After 1 wk of a rigorously controlled sleep-wake schedule and behaviors, 10 healthy participants completed a randomized crossover protocol in dim light and constant conditions, incorporating a night of 6 h of sleep opportunity and a night of immobility while they were supine and awake. VEF was measured in the dominant brachial artery as flow mediated dilation (FMD) before and after each 6-h trial. To avoid disturbing sleep and posture of the participants, blood was drawn using a 12-ft catheter from an adjoining laboratory room before, during, and after each 6-h trial, and plasma was analyzed for markers of oxidative stress [malondialdehyde adducts (MDA)], and endothelin-1. Contrary to expectation, both nocturnal sleep and nocturnal inactivity significantly increased FMD ( P < 0.05). There was no significant change in MDA or endothelin-1 within and between trials. Contrary to expectations based on prior studies, we found that overnight sleep or the inactivity that accompanies sleep did not result in attenuation in VEF in the morning hours in healthy people. Thus, it is plausible that the endogenous circadian system, a remaining factor not studied here, is responsible for the commonly observed decline in VEF across the night.

Are we underestimating the lifelong benefits of therapy for obstructive sleep apnea

Obstructive sleep apnea (OSA) is a complex disorder involving the cardiovascular (CV), pulmonary, and metabolic systems. Characterized by marked daytime fatigue and reduced quality of life, OSA is independently associated with increased risk of hypertension,1 cardiovascular disease (CVD),2 including myocardial infarction (MI)3 and ischemic stroke,4 metabolic syndrome,5 and all-cause mortality.6 Currently, the most common treatment for OSA is continuous positive airway pressure (CPAP) during sleep, though its efficacy in reducing daytime fatigue and CVD risk factors depends largely on compliance to therapy, which is poor in the general population.7 Lamberts et al8 performed a large epidemiological study of OSA, using the Danish National Patient Registry (NPR; ~4.5 million; including 25,389 people diagnosed with OSA), which confirmed associations between OSA and risk of ischemic stroke and MI. Yet, that study failed to show that CPAP reduces the incidence of these adverse CV events.8 On the other hand, a more recent study, which examined the same Danish NPR across a very similar time period, revealed that in people with OSA, CPAP reduces all-cause mortality.9 This editorial evaluates these seemingly conflicting results, whereby CPAP appears to reduce mortality but not two of the largest contributors to mortality: stroke and MI. Of interest, the study by Lamberts et al found that the associations between OSA and risk of MI and ischemic stroke occurred only in young people (aged 18–49 years).8 However, the prevalence of OSA in this sample was only 0.7%, which is lower than in most other random populations (3%–7%).10 Thus, many people with undiagnosed OSA likely contributed to the NPR control group, thereby biasing toward the null hypothesis and perhaps explaining the lack of an OSA effect in the older groups. Additionally, these authors were unable to find an effect of CPAP on stroke or MI incidence in any age-group. However, they do suggest that use of CPAP in the younger population with high CV risk warrants further investigation. This seems reasonable, especially considering possible benefits of CPAP on symptoms of daytime sleepiness,11 plus the known CV benefits of CPAP, including reductions in both nocturnal and daytime blood pressure.12–14 Thus, starting therapy earlier in life has a greater potential to reduce the long-term effects of OSA on the CV system, including reducing the burden of hypertension.15 Should CPAP also be recommended for older people with OSA for CV outcomes alone? Lamberts et al8 claim that OSA may have less of a role in the development of CVD in the elderly because the emergence of other CV risk factors, including hypertension, may attenuate the relative contribution of OSA to MI and stroke. However, given the findings by Jennum et al,9 we believe a reinterpretation is warranted. This newer analysis revealed that CPAP therapy improves survival rate by approximately 30% in middle-aged and elderly men.9 Furthermore, two main limitations of this study may have resulted in an underestimate of the benefits of CPAP, as partly acknowledged by these authors. First, there was no information on the severity of sleep apnea (eg, the apnea-hypopnea index [AHI]). Since people with more severe symptoms are more likely to be treated, we contend that the group that received CPAP likely had higher OSA burden at the onset of the study. If the disease burden was higher and yet survival improved, then the benefits of CPAP would be underestimated. Second, there was no information on CPAP adherence: if adherence was poor yet survival improved, this would also underestimate the potential benefit of consistently used CPAP. Additionally, Jennum et al failed to find an effect of CPAP in the younger cohort (aged 20–39 years) and in women of any age. But, given the protective CV effect female sex has prior to menopause,16 and the relatively low inherent risk of dying in the young, we would not expect CPAP therapy to affect mortality rates in populations with such low vulnerability (given the short duration of the study relative to life expectancy). Taken together, we feel these studies provide strong evidence for the benefits of CPAP therapy across the life spans of people with OSA. In the young, CPAP reduces hypertension and may reduce the risk of an early-life adverse CV event.8 In middle-aged and elderly people with OSA, CPAP improves overall survival possibly via similar effects on the CV system.9 Such beneficial effects of CPAP could presumably be extrapolated to any other therapy that reduces the AHI. There are numerous other emerging therapies for OSA17 and great effort to improve adherence to CPAP therapy.18 Thus, future clinical trials of therapies for OSA ideally should employ large population approaches, and include randomized comparative-effectiveness trials, or placebo-controlled trials (eg, The Apnea Positive Pressure Long-term Efficacy Study).19 Additionally, incorporation of information on adherence to therapy, plus important health status indicators such as blood pressure, AHI, and body mass index will aid investigation of the associations between OSA disease burden, CV risk, and the effect of therapy on survival.

Response to Comment on: van Dijk et al. Exercise Therapy in Type 2 Diabetes: Is Daily Exercise Required to Optimize Glycemic Control? Diabetes Care 2012;35:948–954

We read with great interest the recent article by van Dijk et al. (1) supporting the importance of exercise in the treatment of diabetes. The authors deserve credit for conducting a difficult study on a topic that is of interest to researchers and clinicians alike. We wish to comment on the study design as well as important findings of the study that were overlooked in the manuscript. Authors compared the glucose control between daily exercise (DE) (30 min) to exercise done every other day (EEOD) (60 min). We compliment the authors for controlling …