Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation

Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation

Sleep Medicine 14 (2013) 1277–1282 Contents lists available at ScienceDirect Sleep Medicine journal homepage: www.elsevier.com/locate/sleep Origina...

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Sleep Medicine 14 (2013) 1277–1282

Contents lists available at ScienceDirect

Sleep Medicine journal homepage: www.elsevier.com/locate/sleep

Original Article

Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation Siyavash Joukar a,b,c,⇑, Soodabe Ghorbani-Shahrbabaki d, Vahid Hajali a, Vahid Sheibani b, Nooshin Naghsh d a

Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran c Department of Physiology and Pharmacology, School of Medicine Kerman University of Medical Sciences, Kerman, Iran d Department of Biology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran b

a r t i c l e

i n f o

Article history: Received 4 February 2013 Received in revised form 5 June 2013 Accepted 2 July 2013 Available online 8 September 2013 Keywords: REM sleep deprivation Corticosterone Blood pressure Ventricular tachycardia Ventricular fibrillation Arrhythmia severity

a b s t r a c t Background: According to some reports regarding the increase of cardiac events following sleep deprivation, our study was conducted to clarify the effects of rapid eye movement (REM) sleep deprivation on susceptibility to lethal ventricular arrhythmias in rat. Methods: The animal groups included the control group; the sham 48 and sham 72 groups (without sleep deprivation); and the test 48 and test 72 groups, who experienced REM sleep deprivation for 48 h and 72 h, respectively. For induction of cardiac arrhythmia, aconitine was infused via the tail vein of the animals. Results: After 72 h of REM sleep deprivation, the blood pressure (BP) levels and the QTc interval of the electrocardiogram (ECG) were significantly increased (P < .05 and P < .01, respectively). However, the sleep deprivation had no significant effect on the heart rate (HR), myocardial oxygen consumption index, and plasma corticosterone level. Furthermore, sleep deprivation increased the latency times of premature ventricular contraction (PVC), ventricular tachycardia (VT), and also the PVC number; however, it did not increase the number, duration, and severity of VT and ventricular fibrillation (VF). Conclusion: Our findings suggest that 72 h of REM sleep deprivation is associated with increased risk for hypertension and QT interval prolongation under nonstressful conditions; however, it does not increase the susceptibility to lethal ventricular arrhythmia in rat. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Nowadays, individuals live in so-called sleep-deprived societies. Evidence shows that sleep time has been reduced to1.5 h per day and this decline is a continuing trend [1]. Increase in environmental light, long work days, shifts and night work, as well as the emergence of television, radio, and Internet use in individuals’ lives are some responsible factors affecting the sleep duration [2]. In addition, some sleep disorders such as obstructive sleep apnea (OSA) are associated with partial sleep deprivation [3]. Moreover, OSA and most sleep deprivation occur during the paradoxical stage of sleep [4,5]. Epidemiologic studies reported a U-shaped relationship between sleep duration and mortality by which it was concluded that both sleep excess and sleep deprivation are a threat to survival [6]. Short sleep duration is associated with an increased risk for cardiovascular diseases and diabetes mellitus [6,7]. Although the ⇑ Corresponding author. Address: Neuroscience Research Center, Physiology Research Center and Department of Physiology and Pharmacology, School of Medicine, Kerman University of Medical Sciences, P.O. Box 7616914115, Kerman, Iran. Tel./fax: +98 341 3220081. E-mail addresses: [email protected], [email protected] (S. Joukar). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.07.008

exact mechanism is not clear, redox imbalance [8], elevation of endothelin levels [9], alteration in activity of the sympathetic nervous system [10,11], impairment of endothelium-dependent vasodilation [12], and activation of inflammatory processes [13–15] are some possible reasons. There are some speculations about the increased risk for cardiac arrhythmias in sleep-deprived individuals in the literature, and it has been reported that sleep deprivation may contribute to the development or recurrence of arrhythmias [16,17]. Still this association property is not clear, and to the best of our knowledge no study in the literature has directly investigated the effects of sleep deprivation on the development of lethal cardiac arrhythmia. Therefore, our study aimed to challenge the validity of the proarrhythmic effect of sleep deprivation and clarifying the effects of rapid eye movement (REM) sleep deprivation on blood pressure (BP) and also the susceptibility to lethal ventricular arrhythmias using an animal experimental model.

2. Material and methods Our study was conducted according to the national guidelines for animal studies (Ethical Committee of the Kerman Neuroscience

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Research Center (EC/KNRC/90/6 – Kerman University of Medical Sciences). We included 80 male Wistar rats aged 3 months that weighed 250–350 g and were housed in a temperature-controlled room and were allowed free access to rat regular diet and water. Animals were randomly divided into five groups with 16 animals in each group as follows: (1) the control group (CTL), which were maintained in home cages without sleep deprivation; (2) two sham groups (i.e., S48 and S72), which were kept in a wide platform for 48 h and 72 h, respectively, without sleep deprivation; and (3) two paradoxical sleep-deprived groups (i.e., T48 and T72), which were kept in small platform for 48 h and 72 h, respectively. 2.1. Paradoxical sleep deprivation (REM sleep deprivation) Paradoxical sleep deprivation (PSD) was applied by a multiple platform model. The apparatus contained a water chamber (90 cm  50 cm  50 cm) and two parallel rows (10 cm apart, edge to edge) of 10 circular platforms (10 cm [height], 7 cm [diameter], rising 2 cm above the water surface). When the animals (four rats) were placed within the multiplatform chamber, they moved freely with the least immobilization stress [18]. At the onset of each REM episode the animals were touched or fell into the water due to the loss of muscle tone, and thus were awakened. To test the possible environmental stresses, we also used a wide platform (15 cm [diameter]), which allowed the rats to sleep without falling into the water. The environment of apparatus during the experiments was controlled similar to cages with temperature (23 ± 1 °C) and a light–dark cycle (lights on, 07:00 am–7:00 pm), with free water access and chow pellets hanging from the top of the chamber [19]. 2.2. Measurement of plasma corticosterone At the end of the experiment (between 8:10 am and 8:30 am) under deep anesthesia, six animals of each group were killed and blood samples were collected. Then samples were centrifuged at 4 °C for 15 min at 2600g for isolation of plasma. The level of corticosterone in each sample was assessed by an ELISA kit specific to rat and mice (DRG International Inc., USA) with 0.25 ng/mL sensitivity [20]. 2.3. Measured and calculated parameters Ten rats from each group were considered for the assessment of hemodynamic parameters and arrhythmia susceptibility. The animals were anesthetized with intraperitoneal sodium thiopental (50 mg/kg) [21]. The right common carotid artery was cannulated by a filled polyethylene 50 tube (saline with heparin 15 IU/mL), which was connected to a pressure transducer and a PowerLab system (AD Instruments, Australia); the heart rate (HR) and arterial BP were continuously recorded during the experiment. The trachea was cannulated and animals were artificially ventilated with room air at 50 strokes per minute (stroke volume, 0.8 mL/100 g of body weight) during arrhythmia induction. The electrodes of electrocardiogram (ECG) lead two were attached to the limbs of the animals. An angiocath with gauge 24 was inserted into the lateral vein of the animal tail and then connected to a syringe containing arrhythmogenic drug (aconitine) by an appropriate tube. The time window for the animal recovery from surgery was 15 min, and the basal ECG and BP were recorded following recovery. The animals with cardiac arrhythmia or with a sustained drop in mean arterial BP below 70 mmHg during the stabilization period were excluded from the study. The mean arterial pressure (MAP) was calculated using the MAP = Pd + (Ps Pd)/3 formula, in which Pd is the diastolic arterial pressure and Ps is the systolic arterial pressure. Pressure-rate product (PRP), an indirect measure of myocardial oxygen demand, was

determined as the product of the HR and mean arterial pressure ([MAP⁄HR]⁄1000 1). The PR and QT interval of basal ECG in each group was determined by a mean of 1 min of ECG-recorded strip. Corrected QT (QTc) interval was measured using Bazett’s formula normalized as QTcn-B = QT/(RR/f)1/2, in which RR is R–R interval and f = 150 ms [22,23].

2.4. Arrhythmia induction After basal recording of hemodynamic and ECG for arrhythmia induction, aconitine (from Sigma, England) was infused in the tail vein with a microinfusion pump at a velocity of 0.1 mL per minute (15 lg/mL in saline) [24] for ten minutes. The BP and ECG were simultaneously recorded during the infusion, and this process continued for another 5 min after the infusion period was over. During the 15 min of the experiment, the episodes of premature ventricular contraction (PVC), salvo, and ventricular tachycardia (VT) and ventricular fibrillation (VF) were counted and the latency and duration of PVC, VT, and VF were measured in seconds. According to the Lambeth conventions, ventricular arrhythmias were defined as premature ventricular beats (PVB) or PVCs, discrete and identifiable premature QRS complexes, salvo, two or three consecutive PVBs, VT, a run of four or more consecutive PVBs, or VF, which were all signals of when individual QRS deflections could not easily be distinguished from each other and when the rate could no longer be measured [25]. The threshold dose of aconitine required for producing different ventricular arrhythmias (e.g., PVC, VT, VF) was determined according to the following formula: threshold (lg/kg) for arrhythmia = 15 lg/mL  0.1 mL/minutes  time required for arrhythmia (min)/body weight (kg) = 1.5 lg/minutes  time (min)/body weight (kg). In addition, the severity of arrhythmias in the different groups was quantitatively presented by a scoring system [23] (0, <10 PVCs; 1, P10 PVCs; 2, 1–5 episodes of VT; 3, >5 episodes of VT or 1 episode of VF; 4, 2–5 episodes of VF; and 5, >5 episodes of VF).

2.5. Statistical analysis The results were presented as mean ± standard error of the mean. Comparison of corticosterone levels, HR, BP, and PRP, RR interval, PR interval, QT, QTcn and latency among different groups was performed using one-way analysis of variance and post hoc Tukey tests. Arrhythmia episodes, duration of arrhythmia, threshold dose of aconitine, and scores in the animal groups were compared using nonparametric Kruskal–Wallis and Mann–Whitney U tests. A P value <.05 was considered as statistically significant.

3. Results 3.1. Plasma corticosterone levels The corticosterone levels showed no differences among the control, sham, and sleep-deprived animal groups (Table 1).

3.2. HR, BP, and PRP The index of myocardial oxygen consumption (PRP) and HR did not show any significant differences among the different groups (Table 1). REM sleep deprivation for 72 h significantly increased the systolic and mean arterial blood pressure compared to the control group (144 ± 5 and 125 ± 3 vs 120 ± 5 and 106 ± 5 mmHg, respectively) (P < .05). Moreover, BP was significantly higher in group T72 than in groups S48 and T48 (P < .05) (Fig. 1).

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Table 1 Plasma corticosterone level, myocardial oxygen demand index (pressure-rate product), heart rate, RR interval, and PR interval of electroencephalogram in different groups. Groups

PRP

Heart rate (beats/min)

RR interval (ms)

PR interval (ms)

Plasma corticosterone (ng/mL)

CTL S48 S72 T48 T72

42 ± 2 41 ± 2 43 ± 3 41 ± 4 47 ± 2

412 ± 9 383 ± 14 373 ± 14 393 ± 15 378 ± 9

146 ± 3 158 ± 6 162 ± 6 154 ± 6 159 ± 4

43.8 ± 1.6 44.6 ± 0.4 46.2 ± 1.2 44.8 ± 1.1 45.3 ± 0.8

266 ± 69 312 ± 88.5 319 ± 89 283 ± 62 258 ± 63

Abbreviations: CTL, control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group; PRP, pressure-rate product ([MAP⁄heart rate]⁄1000 These parameters did not show significant changes among different groups. Values are mean ± standard error of the mean; n = 6 for corticosterone and 7–8 for others.

1

).

3.3. Basal ECG QT and QTc intervals of basal ECG of sham and test animal groups showed an increasing trend. However, these parameters were only significant in animals with 72 h of REM sleep deprivation when compared with the control group (72 ± 3 and 70 ± 3 vs 52 ± 2 and 53 ± 3 ms, respectively) (P < .01) (Fig. 2). On the other hand, sleep deprivation was not associated with significant alteration on RR and PR intervals (Table 1). 3.4. Susceptibility to ventricular arrhythmias The PVC numbers were significantly increased in sham and sleep-deprived groups compared to the control animals (P < .05), but the salvo or VF + VT numbers were not (Fig 3). The VF + VT duration was decreased in all groups but only significantly in S48 (P < .05) and S72 (P < .01) groups when compared with the control group (Fig. 4). The latency times from the onset of aconitine infusion to the first PVC, VT, and VF were measured in the different groups. The latency of the induction of PVC was significantly longer in the animals that had previously experienced large platform (without sleep deprivation) and small platform (with REM sleep deprivation) than in the control group (P < .05). The latency of the induction of VT also was significantly longer in the S72, T48, and T72 groups compared to the control group (P < .05). This pattern was repeated for VF latency, but it was not statistically significant (Fig. 5). In addition, threshold dose of aconitine for PVC induction increased in all sham and test groups in comparison to the control groups (P < .05). However, threshold dose of aconitine only increased in the S72 and T48 groups for VT induction when compared with the control group. Despite the relative increase of VF threshold dose, it did not reach a level of significance in all sham

Fig. 2. The QT interval and corrected QT interval as Bazett’s formula normalized (QTcn-B) in each animal group. Abbreviations: CTL, the control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group. Values are expressed in mean ± standard error of the mean; n = 7–8. ⁄⁄P < .01 vs the CTL group.

Fig. 3. The number of ventricular arrhythmias in animal groups. Abbreviations: CTL, the control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group; PVC, premature ventricular contraction; VT, ventricular tachycardia; VF, ventricular fibrillation. Data are expressed in mean ± standard error of the mean; n = 7–8. ⁄P < .05 vs the CTL group.

and test groups (Fig. 6). The score of arrhythmia severity did not show any significant changes in the sleep-deprived animals compared to the control group (Fig. 7).

4. Discussion

Fig. 1. The arterial blood pressure in the different animal groups. Abbreviations: S, systolic blood pressure; D, diastolic blood pressure; MAP, mean arterial pressure; CTL, the control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group. Values are presented as mean ± standard error of the mean; n = 7–8. ⁄P < .05 vs CTL, S48 and T48 groups.  P < .05 compared with the CTL and T48 groups.

In our study, 72 h of REM sleep deprivation led to a significant increase in systolic and mean arterial pressure and a relative but nonsignificant increase in myocardial oxygen consumption index; however, it had no effect on the HR of rats. Moreover, the REM sleep deprivation and corresponding sham groups showed a significant increase in PVC but not in life-threatening ventricular arrhythmias. In addition, the plasma corticosterone levels, as an indicator of hypothalamic–pituitary-adrenal (HPA) axis activity,

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Fig. 4. The duration of ventricular tachycardia + ventricular fibrillation arrhythmias in the different groups. Abbreviations: CTL, the control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group; VT, ventricular tachycardia; VF, ventricular fibrillation. Data are expressed in mean ± standard error of the mean; n = 7–8. ⁄P < .05 vs CTL group. ⁄⁄P < .01 vs the CTL group.

Fig. 5. The latency periods for induction of ventricular arrhythmias. Abbreviations: CTL, the control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group; PVC, premature ventricular contraction; VT, ventricular tachycardia; VF, ventricular fibrillation. Data are expressed in mean ± standard error of the mean; n = 7–8. ⁄P < .05 vs the CTL group.

Fig. 6. Threshold dose of aconitine for induction of ventricular arrhythmias. Abbreviations: CTL, the control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group; PVC, premature ventricular contraction; VT, ventricular tachycardia; VF, ventricular fibrillation. Data are expressed in mean ± standard error of the mean; n = 7–8. ⁄P < .05 vs the CTL group. ⁄⁄P < .01 compared with the CTL group.

were not significantly changed following sleep deprivation. In support of our findings, Neves et al. [26] reported that PSD resulted in a significant increase in BP in rats when using the same method. The other study also showed a significant elevation of systolic BP following 114 h of REM sleep deprivation in rats [27].

Fig. 7. Scores of arrhythmia severity in each experimental group. Abbreviations: CTL, the control group; S48, sham 48 group; S72, sham 72 groups; T48, test 48 group; T72, test 72 group; PVC, premature ventricular contraction; VT, ventricular tachycardia; VF, ventricular fibrillation. Data are expressed in mean ± standard error of the mean; n = 7–8. Scores were defined as 0, <10 PVCs; 1, P10 PVCs; 2, 1–5 episodes of VT; 3, >5 episodes of VT or 1 episode of VF; 4, 2–5 episodes of VF; or 5, >5 episodes of VF.

Human studies also demonstrated similar findings. Gottlieb et al. [28] documented that individuals who slept less than 6 h compared to those who slept 7–8 h at night had a higher MAP [28]. There also has been a considerable association between short sleep duration (<5 h) and a risk for increased BP [29]. However, it has been shown that 1 week of continuous night shift had no significant effect on the mean HR [30]. Furthermore, Kato et al. reported that a single night of sleep deprivation was associated with increased BP and decreased muscle sympathetic nerve activity, but it had no effect on the HR. The authors concluded that the hypertension response following sleep deprivation was not the result of vasoconstriction derived from increased sympathetic stimulation of the muscles [11]. Consistent with previous research, our results revealed that there are mechanisms other than increases in HR that are responsible for the increase in arterial BP induced by paradoxical sleep deprivation. Some previous studies suggested that sleep deprivation may induce the HPA axis hyperactivity, which in turn contributes to the secondary pathology such as insulin resistance and hypertension [31]. On the other hand, Thamaraiselvi et al. [32] recently showed that plasma corticosterone levels were decreased to the basal level by the end of 96 h REM sleep deprivation in rats, despite a primary increase. Accordingly, because there was no significant change in the corticosterone levels of the sleep-deprived animals, the increase in BP following PSD in our study cannot be attributed to the stress effects, which are reflected by the HPA axis hyperactivity. One possible reason for the increase in BP after sleep deprivation is the resetting of the baroreceptor system to a higher BP, in which the new setting of baroreflex can cause an increase in the arterial BP [10]. Alternative factors may include an increase in the activity of the renin–angiotensin system or an increase in the production of vasoconstrictors, such as endothelin. Another plausible mechanism for elevated BP after sleep deprivation may be derived from some physiologic alterations including increased vascular sympathetic activity or strengthened neural responses of circulation. Because the index of myocardial oxygen consumption (PRP) is the product of the HR and mean BP and because the former was not changed, the relative increase in PRP in animals following 72 h of PSD was predictable. However, an increase in arterial BP along with the relative increase of myocardial oxygen demand can enhance the risk for cardiovascular events in the long term. From the point of view of the ECG, 72 h of REM sleep deprivation was associated with a significant increase in QTc interval and a relatively nonsignificant increase in PR interval. To the best of our knowledge, there is no animal study of sleep deprivation in which the QT or PR interval measurements have been reported in the literature to date. However, some human

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studies documented prolongation of QT interval and QT interval dispersion following sleep disturbances, which is in agreement with our findings [33,34]. In the other study, Murata et al. [35] also demonstrated that the QTc interval was significantly longer in the shift workers who experienced some degree of sleep disturbances [36]. The elevated BP in the animals that were deprived of REM sleep for 72 h can affect the baroreceptor system, causing changes in the autonomic nervous system output, and hence an increase in the parasympathetic tone. The increased parasympathetic activity is associated with negative chronotropic and dromotropic responses. Although 72 h of sleep deprivation had no significant effect on the HR in our study, the relative increase in PR and the significant increase in QT interval may have resulted from the parasympathetic and sympathetic tonus imbalance. Acquired QT prolongation may be caused by changes in plasma electrolytes, including loss of magnesium, calcium, and potassium [37]. It has recently been reported that insomnia causes diuresis and sodium excretion in humans [38]. PSD also may cause changes in the expression of sodium, calcium, and potassium protein channels responsible for depolarization and repolarization of the heart muscle cells, and thereby prolong the QT interval for which further studies are required to prove. The REM sleep deprivation and corresponding sham groups showed a significant increase in PVCs. The numbers of salvo, VT + VF, and VT + VF duration were nonsignificantly reduced, though the latency periods for PVC and VT were significantly increased following REM sleep deprivation. Interestingly the decline in VT + VF duration and also the latency prolongation for PVC and VT were significant in sham groups. In addition, the threshold dose of aconitine to induce PVC, VT, and VF not only did not decrease, but it actually increased in some cases in both PSD and sham animals. Our finding in terms of increase in PVC in sleep-deprived animals is in agreement with an experimental study on the rats in which 48 h sleep deprivation increased the premature ventricular beats [17]. Furthermore, a human study showed that despite the lack of increase in HR, the PVC count was significantly higher in shift workers after 1 year [39]. The increased PVC number in sham groups raises the suspicion that changes in environment can lead to passive stress in animals that may trigger physiologic mechanisms, which in turn activate the ectopic foci in the heart. The stress effector systems include the autonomic nervous system, the adrenomedullary hormonal system, the HPA axis, the renin–angiotensin– aldosterone system, and the vasopressin system [40]. Consistent with previous studies [19], the possibility of HPA axis hyperactivity was minimized, as there were no significant changes in plasma corticosterone levels of animal groups; however, the activation of other stress effector systems was probable in our study. On the other hand, all animals that were placed within the multiplatform chamber showed an increase of QT interval, which was only significant in the group with 72 h of sleep deprivation. Long QT intervals that stem from an increase in the action potential duration and effective refractory period are one of the mechanisms of antiarrhythmic drugs class 3, which thereby prevent the reentry phenomenon and the occurrence of the lethal cardiac arrhythmia [41]. Obviously the mere increase in PVC without the reentry phenomenon cannot lead to fatal cardiac arrhythmias. Thus it is likely that partial QT interval prolongation is one of the potential mechanisms involved in the increase of the latency time and even reduction in the duration of lethal cardiac arrhythmias of sham and sleep-deprived animals. Yet the increased risk for arrhythmias in the presence of the extremely long QT interval should not be ignored, especially in stressful situations [42]. Further studies are needed to elucidate the exact mechanisms responsible for the

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modulatory effects of REM sleep deprivation on fatal ventricular arrhythmia. Although corticosterone measurements rule out the HPA axis involvement, we did not assess the contribution of other stress effector systems in the results of our study. Additionally we only evaluated the effects of subchronic sleep deprivation, but we did not evaluate the effects of chronic REM sleep deprivation on the propensity to malignant ventricular arrhythmia and ECG parameters. We plan to address these issues and limitations in our future works. Our findings suggest that 72 h of REM sleep deprivation in low stress conditions is associated with an increase in the BP, but it does not increase the susceptibility of the lethal cardiac arrhythmias in rats. If these observations could be extrapolated to humans by monitoring BP and ECG and by decreasing workplace stress, the risk for life-threatening ventricular arrhythmias would be reduced in individuals with insufficient sleep. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.07.008.

Acknowledgments The authors are thankful to the Kerman Neuroscience Research Center (KNRC/90/6), Kerman, Iran, for financial support of the project; and Professor Hamid Najafipour for his good cooperation; and Ms Nadia Ghazanfari Moghaddam for her critical proof-reading of the manuscript. The data presented in this article are from a Master thesis (Soodabe Ghorbani-Shahrbabaki) performed in the Department of Physiology and Neuroscience Research Center of School of Medicine Kerman University of Medical Sciences, Kerman, Iran. References [1] Rajaratnam SM, Arendt J. Health in a 24-h society. Lancet 2001;358:999–1005. [2] Chokroverty S. Sleep disorders medicine: basic science, technical considerations, and clinical aspects. 2nd ed. Boston (MA): Butterworth and Heinemann; 1999. p. 14–16. [3] Cheshire K, Engleman H, Deary I, Shapiro C, Douglas NJ. Factors impairing daytime performance in patients with sleep apnea/hypopnea syndrome. Arch Intern Med 1992;152:538–41. [4] Bear MF, Connors BW, Paradiso MA. Neuroscience exploring the brain. Maryland: Lippincott Williams & Wilkins; 1996. p. 666. [5] Lavie P, Silverberg D, Oksenberg A, Hoffstein V. Obstructive sleep apnea and hypertension: from correlative to causative relationship. J Clin Hypertens 2001;3:296–301. [6] Wolk R, Gami AS, Garcia-Touchard A, Somers VK. Sleep and cardiovascular disease. Curr Probl Cardiol 2005;30:625–62. [7] Nagai M, Hoshide S, Kario K. Sleep duration as a risk factor for cardiovascular disease—a review of the recent literature. Curr Cardiol Rev 2010;6:54–61. [8] Everson CA, Laatsch CD, Hogg N. Antioxidant defense responses to sleep loss and sleep recovery. Am J Physiol Regul Integr Comp Physiol 2005;288:374–83. [9] Palma BD, Gabriel Jr A, Bignotto M, Tufik S. Paradoxical sleep deprivation increases plasma endothelin levels. Braz J Med Biol Res 2002;35:75–9. [10] Ogawa Y, Kanbayashi T, Saito Y, Takahashi Y, Kitajima, Kenichi Takahashi K, et al. Total sleep deprivation elevates blood pressure through arterial baroreflex resetting. a study with microneurographic technique. Sleep 2003;26:986–9. [11] Kato M, Phillips BG, Sigurdsson G, Narkiewicz K, Pesek CA, Somers VK. Effects of sleep deprivation on neural circulatory control. Hypertension 2000;35:1173–5. [12] Takase B, Akima T, Satomura K, Ohsuzu F, Mastui T, Ishihara M, et al. Effects of chronic sleep deprivation on autonomic activity by examining heart rate variability, plasma catecholamine, and intracellular magnesium levels. Biomed Pharmacother 2004;58:35–9. [13] Meier-Ewert HK, Ridker PM, Rifai N, Rifai N, Regan MM, Price J, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 2004;43:678–83.

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