The Effect of Sleep Deprivation on Coronary Heart Disease△

Rong Yuan, Jie Wang*, and Li-li Guo



The Effect of Sleep Deprivation on Coronary Heart Disease△

Rong Yuan1,2, Jie Wang1*, and Li-li Guo1

1Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 1000532Beijing University of Chinese Medicine, Beijing 100029

Sleep deprivation (SD) has been associated with an increased morbidity and mortality of coronary heart disease (CHD). SD could induce autonomic nervous dysfunction, hypertension, arrhythmia, hormonal dysregulation, oxidative stress, endothelial dysfunction, inflammation and metabolic disorder in CHD patients. This paper reviewed the study results of SD in clinical trials and animal experimentsand concluded that SD was associated with cardiovascular risk factors, which aggravated CHD in pathogenesis and outcomes.

heart disease; insomnia; sleep disorder; risk factors; myocardial ischemia

Chin Med Sci J 2016; 31(4):247-253

LEEP deprivation (SD) represents loss of sleep and short of sleep duration. It can be divided into partial sleep deprivation (PSD), total sleep deprivation (TSD), acute sleep deprivation (ASD) and chronic sleep deprivation (CSD) according to time and duration. In addition, according to sleeping state, it is divided into rapid eye movement sleep deprivation (REMSD) and non-rapid eye movement sleep deprivation (NREMSD). SD has been associated with increased cardiovascular morbidity and mortality in epidemiologic and case-control studies.1It has been suggested that sleep duration is an independent predictor for morbidity and mortality of cardiovascular disease.2Many studies have indicated that the incidence of coronary heart disease (CHD) appears an obvious negative correlation with sleep duration, and SD has been related to a great risk of myocardial infarction and heart failure.3-7Results of Coronary Artery Risk Develop- ment in Young Adults (CARDIA) study showed that short sleeping time is associated with coronary artery calcifica- tion, a precursor of CHD,8and SD has been regarded as a marker of subclinical heart disease.9

Therefore, it is important to understand the effects of SD on pathogenesis, progress and prognosis of CHD. This paper summarized the effects of SD on CHD in terms of autonomic nervous dysfunction, hypertension, arrhythmia, hormonal dysregulation, oxidative stress, endothelial dys- function, inflammation and metabolic disorders.

Autonomic Nervous Dysfunction

Autonomic nervous system was significantly modula- ted by age, environmental conditions, and activities undertaken. Studies have shown that SD can increase the sympathetic outflow to the heart or periphery through increasing catecholamine, coronary vasomotor tone, blood pressure and heart rate, thus alter the balance between demand and supply of oxygen.1,10Autonomic nervous dysfunction and activation of the sympathetic nervous system are primary contributors to cardiovascular disease, which can lead to excessive vasoconstriction, fibrosis, and cardiac remodeling.11

Large quantities of researches have suggested that SD has important effects on sympathetic nervous system of the heart. Zhong12studied 18 healthy adult and found that, heart rate, low-frequency components of heart rate variability and blood pressure variability were all increased after 39 hours of SD, while baroreflex sensitivity was decreased. Another study with 12 healthy males showed that, heart rate, systolic blood pressure and the low-frequency components of heart rate variability were increased significantly within 32 hours of TSD.13Further- more, Dettoni JL14investigated 5 nights of PSD (<5 hours per night) in 13 healthy male volunteers, found that high-frequency components of heart rate variability decreased in percentage, low-frequency components of heart rate variability increased in percentage, low-frequency band of blood pressure variability and serum norepine- phrine also increased as well. Recently, Tobaldini E15measured heart rate variability, blood pressure variability and baroreflex sensitivity in 15 healthy residents of Internal Medicine Department and found a sympathetic activation and a parasympathetic withdrawal after one night of ASD. It was reported that ASD blunted cardio- vascular autonomic response and impacted autonomic regulation of cardiac function.16It was also reported that 40 hours of TSD had a worse deleterious effect on the autonomic nervous system in older women than in young women.17

Hypertension

More and more evidences have suggested the close relationship between short sleeping time and hyperten- sion.18SD can increase sympathetic nerve activation with a high catecholamine level, leading to hypertension under the synergistic effects of norepinephrine, renin-angiotensin system and endothelin.1,19Hypertension elevates afterload pressure and exacerbates cell death, which aggravates myocardial ischemic and increases the risk of cardiovas- cular events.18,20

Many studies have shown a strong association between SD and the development of hypertension. Irwin MR9found that PSD induced great increase of heart rate, nore- pinephrine and epinephrine levels in the alcohol-dependent men. Robillard R and colleagues observed the effect of SD on blood pressure and its response, found that half of the subjects, both young and elderly, showed hypertensive responses instead of systolic blood pressure dropping when transitioning from semi-recumbent to standing. In the semi-recumbent position, blood pressure showed a notable increase in the elderly group but not in the young group, and 25% of normotensive elderly subjects had remarkable systolic hypertension of >140 mmHg after one night of SD.21Carter JR et al investigated the heart rate, blood pressure and muscle sympathetic nerve activity in 30 healthy subjects. The results showed both male and female presented increases of systolic, diastolic and mean blood pressure after 24 hours of TSD, while reduced muscle sympathetic nerve activity was only observed in males. Another study had similar results showing that TSD- induced hypertension occurred in both male and female, but only men had sympathetic baroreflex dysfunction.22As a result, the effects of SD on hypertension might be depen- dent on age, gender, alcohol-dependence, measurement postures and deprived time.

Arrhythmia

It has been shown that SD can increase the incidence of arrhythmia by damaging the inherent biological rhythms and causing physical stress,23and arrhythmia is the main cause of CHD mortality. The ventricular tachycardia, ventricular fibrillation and atrioventricular block are fatal arrhythmia in CHD, and heart rate variability has high predictive value in malignant arrhythmia.

Studies have revealed that cardiac arrhythmia has close relationship with SD. Walker AD24discovered that respiratory sinus arrhythmia was increased after 28 hours of SD. Joukar S25found that blood pressure levels and the QT interval of the electrocardiogram increased significantly after 72 hours of REMSD, the latency times of premature ventricular contraction and ventricular tachycardia increased significantly as well, which indicates the increased risk for CHD. In addition, Chen WR26studied 60 young healthy subjects who had 24 hours of SD, and found that the ratio of low frequency to high frequency of heart rate variability was increased compared with the normal sleeping controls. Some subjects also presented mild palpitation due to premature atrial beats and premature ventricular contraction after SD. Another study have reported that ASD affected left ventricle diastolic function and increased QT intervals, T wave peak-to-end (TpTe) intervals, and TpTe/QT ratios in healthy young adults.27An experimental study reported that SD significantly prolonged the action potential duration of ventricular myocytes in rats, which may con- tribute to the development and recurrence of ventricular arrhythmias.28

Hormonal Dysregulation

It has been reported that SD could disrupt secretion of hormones and metabolites，which affected neuroendocrine in patients with CHD. During period of SD, melatonin rhythm was substantially disturbed, renin angiotensin system was activated, metabolite rhythms was disarrange, accompanied with changes of catecholamine, cortisol, rennin, angiotensin, thyroid stimulating hormone and other metabolites. These disorders may impair endothelial function and baroreceptor control function, lead to hyper- tension and platelet activation.1

Studies have demonstrated that the serum melatonin concentration significantly decrease during the deprived night in CHD patients.29,30 A variety of hormones and metabolitescould affect the incidence and prognosis of CHD, and melatonin plays an important role in the mechanism of SD aggravating CHD. Andersen ML31studied the plasma catecholamines, testosterone, estrone, progesterone, prolactin, corticosterone and adrenocorti- cotropic hormone concentrations in rats after 4 days of SD, and found that almost all hormones levels in plasma altered after 24 hours of SD, while estrone level decreased and prolactin level increased after 96 hours of SD. In addition, SD could activate the renin angiotensin system. Sun X32investigated serum rennin, angiotensin and cortisol levels after 24 hours of SD in 160 servicemen who were 18 to 30 years old. The results showed that serum rennin, angiotensin Ⅱ and cortisol levels were significantly higher than that before SD. Cardiac renin-angiotensin system could also lead to various arrhythmias in myocar- dial ischemia-reperfusion by activating excessive norepine- phrine release.33In addition, Davies SK34examined the effect of 24 hours of ASD on plasma metabolite rhythms in 12 healthy young men. Among 171 quantified metabolites of daily rhythm, 27 metabolites including tryp- tophan, serotonin, taurine, 3 sphingolipids, 8 acylcarni- tines and 13 glycerophospholipids raised significantly after SD.

Oxidative Stress

Many studies have indicated that SD could aggravate myocardial ischemia-reperfusion injury through oxidative stress by increasing energy consumption and decreasing antioxidant capacity, as well as increasing free radical accumulation and aggravating endoplasmic reticulum stress.35It has been shown that SD weakens the organ specific molecular functions and increases cellular metabolic stress in heart, especially the endoplasmic reticulum stress,36which leads to apoptosis in ischemia- reperfusion injury and atherosclerosis.

SD has been found to be related to oxidative stress, which is one of the major causative factors of ischemia- reperfusion injury in CHD. Everson CA37studied major enzymatic antioxidants including catalase, glutathione per- oxidase and indexes of glutathione recycling after 5 days of SD, showing that SD can increase the rate of oxidative pentose phosphate pathway activity and induce the oxidative stress in heart. Chai HJ38investigated elec- trocardiogram, myocardium morphology changes, MDA content and SOD activity of myocardial mitochondria in 35 rats after 2, 4 and 5 days of SD respectively, and found that the subcellular organelles were impaired in different degrees, in addition, lipid peroxidation spread widely with increase of MDA level and decrease of SOD activity. This result indicated that SD could induce oxygen stress damage on myocardium. Chen H39investigated the effect and mechanism of SD induced-myocadial injury, found that 5 days of ASD could increase the hemodynamic measurements and the phosphorylation of protein kinase, and caused over expression of Bax protein. Another study showed that 4 days of SD inhibited cardiac function and leaded to less tolerance to ischemia-reperfusion injury, which may cause excessive nitric oxide in heart.40

Endothelial Dysfunction

SD has been established as a cause of endothelial dysfunction, which aggravates atherosclerosis and CHD. A large number of studies have reported that SD impaired the endothelial function with high level of endothelin by activating hypothalamus-pituitary-adrenal axis, which plays an important role in the pathological process of CHD. High level of endothelin with the vasoconstriction effects could decrease local blood flow and increase neutrophile granu- locyte and adhesion molecules, which induced athe- roscle- rosis and thrombosis.19,41

Palma BD19investigated the plasma endothelin- 1/2 in SD model of male rats, revealed that 96 hours of SD induced a significant increase in endothelin-1/2 release compared to normal sleep group. The high level of endothelin contributes to the endothelial dysfunction. Sauvet13concluded that SD caused vascular dysfunction after assessing endothelium-dependent and -independent cuta- neous vascular conductance in 12 healthy males during 40 hours of TSD. He and his colleagues found that plasma level of E-selectin increased during TSD, while intercellular adhesion molecule-1 and IL-6 increased after one night of sleep recovery. The endothelium-dependent and -indepen- dent cutaneous vascular conductance was significantly decreased after 29 hours of TSD. In addition, they carried out another study investigating the endothelial function after 24 hours of TSD and discovered a reduction in endothelialdependent vasodilation by nitric oxide synthase and cyclooxygenase pathway alterations.42A clinical trial was conducted and showed that 5 nights of PSD was sufficient to cause venous endothelial dysfunction, with sympathetic nerve activation and low bioavailability of nitric oxide dysfunction, which increased the cardiovas- cular risk.14

Inflammation

Studies have suggested that SD could induce inflam- mation and exacerbate myocardial injury. VanLeeuwen43examined 13 healthy young men who had 4 hours sleep per night for 5 nights, demonstrated increases in C-reactive protein, B-cells, peripheral blood mononuclear cell and decrease in NK-cells, accompanied by increased production of IL-1β, IL-6 and IL-17 at mRNA level after SD. This study suggested that PSD could increase lymphocyte activation and induce production of proinflammatory cytokines, which increase the risk of CHD. Tanja Langeand colleagues’ research has suggested that subchronic sleep loss reverses NK-cell activity and proinflamma- tory cytokines such as TNF-α and IL-6, which repre- sents a pathophysiological change during chronic sleep loss.44Another study reported that PSD increased levels of ultrasensitive C-reactive protein and myo- globin in blood, induced the cardiac injure during acute intermittent exercise.45It is believed that increased inflammation factors, such as IL-1, IL-2, IL-6, TNF-α, C-reactive protein, monocytes, neutrophils, phagocytic cells and activity of NK cells, could enlarge the extent of infarct and severe apoptosis in ischemic injury.1,46Proinflammatory mediators and inflammatory cells after SD play an integral part in cardiac injury by triggering myocardial infarction, apoptosis and reperfusion injury.47

Metabolic Disorders

Epidemiological studies have shown that sleep loss and circadian disruption are closely related to the metabolic disorders, including dysregulation of multiple hormone axes, insulin resistance, glucose intolerance, insulin sensitivity reduction and hyperleptinemia.48-51Metabolism disorders after SD may exacerbate oxidative stress and myocardial infarction.52

Many studies have shown that metabolic disorders caused by SD may contribute to metabolism syndrome and increase the risk of CHD. Study by Andersen ML53revealed that various metabolic parameters were associated with cardiovascular risk in young and aged rats. After 96 hours of PSD, triglyceride levels in both young and aged rats dropped, while blood viscosity decreased only in aged rats but not in young rats. Also, significant decrease of very low density lipoprotein was observed in both young and aged animals, whereas significant increases of low density lipoprotein and high density lipoprotein were only observed in aged rats. These data indicated that PSD may intensify certain aging-related effects and had significant but heterogeneous physiological effects on the elderly, which could contribute to the elevated risk of CHD. Kong AP54conducted a cross-sectional population-based study on serum lipid profiles and sleep duration in healthy volunteer students in Hong Kong. The results demonstrated that short sleeping time was not only significantly associated with increased opportunities of high triglyceride and low density lipoprotein levels in secondary school children, but also associated with obesity and atherogenic dyslipidemia in young school children. Clinic studies have shown that 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption could decrease the subjects’ resting metabolic rate, increase plasma glucose concentrations and lead to insulin restriction.48,50Another research has demonstrated that 5 days of ASD could increase blood glucose, glucagon levels and decrease insulin, while insulin-like growth factor-1 administration could reduce the levels of glucagon and blood glucose and rescue the insulin level.39

Summary and Future Directions

SD is associated with increased morbidity and mor- tality of CHD. Studies have demonstrated abnormalities of autonomic function, hormonal profiles, oxidative stress, endothelial function and inflammation in the subjects of SD. The mechanism of these disorders has not been clear yet, but were certainly related to the autonomic nervous function, hypothalamus-pituitary-adrenal axis and renin- angiotensin system. Whether these systems are able to adapt or not over time has not been fully understood, but it is reasonable to assume that SD may be a common and preventable cardiovascular risk factor.

The experimental data reviewed here have suggested that disorders of autonomic tone, blood pressure, hormones,oxidative stress, endothelial function and inflammation response recognized contribute to the development of cardiovascular diseases, most importantly, CHD. All of these changes are relevant to each other, forming a risk factor network of CHD, which is likely to influence on the morbidity and mortality of CHD. Although experimental models used in the studies are varied, such as TSD or PSD, ASD or CSD, REMSD or NREMSD, the magnitude of pathological changes may be predictive for CHD risk in the future and are worthy of further investigation.

It is important to study the difference of pathological response to short-term ASD and prolonged PSD in patho- genesis of CHD, as well as its differences in subgroups of differrent gender and age. Additionally, the inter-relationships among autonomic function, metabolic hormonal changes, oxidative stress, endothelial function and inflammation should be investigated, so that effective medicine interven- tions could be possible. Traditional Chinese medicine is a good choice for its multi-target effects on multiple risk factors of CHD,55and would be promising in prevention and treatment of CHD. In addition, the effect of SD on signal channel of CHD in term of micro RNA has not been clear yet and need further investigation.

1. Mullington JM, Haack M, Toth M，et al. Cardiovascular, inflammatory, and metabolic consequences of sleep deprivation. Prog Cardiovasc Dis 2009; 51: 294-302.

2. Cheng TO. Effect of sleep deprivation on cardiovascular health. Int J Cardiol 2009; 134: 293-4.

3. Cappuccio FP, Cooper D, D'Elia L, et al. Sleep duration predicts cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. Eur Heart J 2011; 32: 1484-92.

4. Singh RB, Pella D, Neki NS, et al. Mechanisms of acute myocardial infarction study (MAMIS). Biomed Pharmaco- ther 2004; 58 Suppl 1: S111-5.

5. Janszky I, Ahnve S, Ljung R, et alDaylight saving time shifts and incidence of acute myocardial infarction- Swedish Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA). Sleep Med 2012; 13: 237-42.

6. Laugsand LE, Vatten LJ, Platou C, et alInsomnia and the risk of acute myocardial infarction: apopulation study. Circulation 2011; 124: 2073-81.

7. Tofield A. Insomnia linked to increased risk of heart failure. Eur Heart J 2013; 34: 1771.

8. King CR, Knutson KL, Rathouz PJ, et alShort sleep duration and incident coronary artery calcification. JAMA 2008; 300: 2859-66.

9. Irwin MR, Ziegler M. Sleep deprivation potentiates activation of cardiovascular and catecholamine responses in abstinent alcoholics. Hypertension 2005; 45: 252-7.

10. Almeida FR, Perry JC, Futuro-Neto HA, et alCardiovas- cular function alterations induced by acute paradoxical sleep deprivation in rats. Clin Exp Hypertens 2014; 36: 567-71.

11. Wright JW, Mizutani S, Harding JW. Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies. Heart Fail Rev 2008; 13: 367-75.

12. Zhong X, Hilton HJ, Gates GJ, et alIncreased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol 2005; 98: 2024-32.

13. Sauvet F, Leftheriotis G, Gomez-Merino D, et alEffect of acute sleep deprivation on vascular function in healthy subjects. J Appl Physiol 2010; 108: 68-75.

14. Dettoni JL, Consolim-Colombo FM, Drager LF, et alCard- iovascular effects of partial sleep deprivation in healthy volunteers. J Appl Physiol 2012; 113: 232-6.

15. Tobaldini E, Cogliati C, Fiorelli EM, et alOne night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians. Eur J Intern Med 2013; 24: 664-70.

16. Cincin A, Sari I, Oğuz M, et al. Effect of acute sleep deprivation on heart rate recovery in healthy young adults. Sleep Breath 2015; 19: 631-6.

17. Virtanen I, Kalleinen N, Urrila AS, et al. Cardiac autonomic changes after 40 hours of total sleep deprivation in women. Sleep Med 2015; 16: 250-7.

18. Calvin AD, Caples SM. Getting to the heart of sleep deprivation. Sleep 2011; 34: 251-2.

19. Palma BD, Gabriel A Jr, Bignotto M, et alParadoxical sleep deprivation increases plasma endothelin levels. Braz J Med Biol Res 2002; 35: 75-9.

20. Mozaffari MS, Schaffer SW. Effect of hypertension and hypertension-glucose intolerance on myocardial ischemic injury. Hypertension 2003; 42: 1042-9.

21. Robillard R, Lanfranchi PA, Prince F, et alSleep depri- vation increases blood pressure in healthy normotensive elderly and attenuates the blood pressure response to orthostatic challenge. Sleep 2011; 34: 335-9.

22. Carter JR, Durocher JJ, Larson RAet al. Sympathetic neural responses to 24-hour sleep deprivation in humans: sex differences. Am J Physiol Heart Circ Physiol 2012; 302: H1991-7.

23. Stamler JS, Goldman ME, Gomes J, et alThe effect of stress and fatigue on cardiac rhythm in medical interns. J Electrocardiol 1992; 25: 333-8.

24. Walker AD, Muth ER, Odle-Dusseau HN, et alThe effects of 28 hours of sleep deprivation on respiratory sinus arrhythmia during tasks with low and high controlled attention demands. Psychophysiology 2009; 46: 217-24.

25. Joukar S, Ghorbani-Shahrbabaki S, Hajali V, et alSusceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation. Sleep Med 2013;14:1277-82.

26. Chen WR, Shi XM, Yang TS, et al. Protective effect of metoprolol on arrhythmia and heart rate variability in healthy people with 24 hours of sleep deprivation. J Interv Card Electrophysiol 2013; 36: 267-72.

27. Cakici M, Dogan A, Cetin M, et al. Negative effects of acute sleep deprivation on left ventricular functions and cardiac repolarization in healthy young adults. Pacing Clin Electro- physiol 2015; 38: 713-22.

（2）通过对竖井、缓斜井两种方案进行分析比较，竖井施工工程量小，工期短，投资低，进度风险可控，本工程推荐采用竖井方案。

28. Fang Z, Ren YP, Lu CY, et al. Effects of sleep deprivation on action potential and transient outward potassium current in ventricular myocytes in rats. Med Sci Monit 2015; 21: 5429.

29. Rao ML, Pelzer E, Papassotiropoulos A, et alSelective slow-wave sleep deprivation influences blood serotonin profiles and serum melatonin concentrations in healthy subjects. Biol Psychiatry 1996; 40: 664-7.

30. Brugger P, Marktl W, Herold M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet 1995; 345: 1408.

31. Andersen ML, Martins PJ, D'Almeida V, et alEndo- crinological and catecholaminergic alterations during sleep deprivation and recovery in male rats. J Sleep Res 2005; 14: 83-90.

32. Sun X, Dai X, Yang T, et alEffects of mental resilience on neuroendocrine hormones level changes induced by sleep deprivation in servicemen. Endocrine 2014; 47:884-8.

33. Mackins CJ, Kano S, Seyedi N, et alCardiac mast cell- derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia- reperfusion. J Clin Invest 2006; 116: 1063-70.

34. Davies SK, Ang JE, Revell VL, et alEffect of sleep deprivation on the human metabolome. Proc Natl Acad Sci USA 2014; 111: 10761-6.

35. Jiang B, Zhao ZX. Oxidative stress induced by sleep deprivation: an update. Acad J Sec Mil Med Univ 2007; 28: 201-3.

36. Anafi RC, Pellegrino R, Shockley KR, et alSleep is not just for the brain: transcriptional responses to sleep in peripheral tissues. BMC Genomics 2013; 14: 362.

37. Everson CA, Laatsch CD, Hogg N. Antioxidant defense responses to sleep loss and sleep recovery. Am J Physiol Regul Integr Comp Physiol 2005;288: R374-383.

38. Chai HJ，Xu SM. Damage effects of sleep deprivation on myocardium and its antioxygen index in rats. Chin J Appl physiol 2008; 24: 71-5.

39. Chen H, Zhao Z, Zheng J, et alThe effect of IGF-1 on symptoms of sleep deprivation in a rat model of inflammatory heart disease and metabolic syndrome. Biochem Biophys Res Commun 2014; 446: 843-9.

40. Jeddi S, Asl AN, AsgariA, et al. The Effect of sleep deprivation on cardiac function and tolerance to ischemia- reperfusion injury in male rats. Arq Bras Cardiol 2016; 106: 41-8.

41. Vinten-Johansen J, Zhao ZQ, Nakamura M, et alNitric oxide and the vascular endothelium in myocardial ischemia-reperfusion injury. Ann N Y Acad Sci 1999; 874: 354-70.

42. Sauvet F, Florence G, Van Beers P, et alTotal Sleep Deprivation Alters Endothelial Function in Rats: A Nonsympathetic Mechanism. Sleep 2014; 37: 465-73.

43. VanLeeuwen WM, Lehto M, Karisola P, et alSleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS One 2009; 4: e4589.

44. Tanja Lange, Stoyan Dimitrov, Jan Born. Effects of sleep and circadian rhythm on the human immune system. Ann N Y Acad Sci 2010; 1193: 48-59.

45. Arbi Mejri M, Yousfi N, Hammouda O, et al.One night of partial sleep deprivation increased biomarkers of muscle and cardiac injuries during acute intermittent exercise. J Sports Med Phys Fitness 2016. [Epub ahead of print]

46. Chao J, Yin H, Yao YY, et alNovel Role of Kallistatin in protection against myocardial ischemia–reperfusion injury by preventing apoptosis and inflammation. Hum Gene Ther 2006; 17: 1201-13.

47. Vinten-Johansen J, Jiang R, Reeves JG, et alInflam- mation, proinflammatory mediators and myocardial ischemia–reperfusion injury. Hematol Oncol Clin North Am 2007; 21: 123-45.

48. Lange T, Dimitrov S, Born J. Effects of sleep and circadian rhythm on the human immune system. Ann NY Acad Sci 2010; 1193: 48-59.

49. Gangwisch JE. Epidemiological evidence for the links between sleep, circadian rhythms and metabolism. Obes Rev 2009; 10Suppl 2:37-45.

50. Buxton OM, Cain SW, O'Connor SP, et alAdverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci Transl Med 2012; 4: 129-43.

51. Buxton OM, Pavlova M, Reid EW, et alSleep restriction for 1 week reduces insulin sensitivity in healthy men. Dia- betes 2010; 59: 2126-33.

52. Bass J, Takahashi JS. Circadian Integration of Metabolism and Energetics. Science 2010; 330: 1349-54.

53. Andersen ML, Martins PJ, D'Almeida V, et al. Effects of paradoxical sleep deprivation on blood parameters associated with cardiovascular risk in aged rats. Exp Gerontol 2004; 39: 817-24.

54. Kong AP, Wing YK, Choi KC, et alAssociations of sleep duration with obesity and serum lipid profile in children and adolescents. Sleep Med 2011;12:659-65.

55. Hu YB, Peng JB, Gu SMolecular docking in Xin-Ke-Shu preparation's multi-target effect on coronary heart disease. Acta Physico-Chimica Sinica 2012; 28: 1257-64.

for publications April 18, 2015.

Tel: +86 010-88001817; fax: +86 1088001817. E-mail address:wangjie0103@126.com

△Supported by National Science and Technology Major Projects for "Major New Drugs Innovation and Development" Foundation (No. 2012ZX09102-201-006).