Published online before print December 29, 2008, doi: 10.1161/HYPERTENSIONAHA.108.125542
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2009;53:251.)
© 2009 American Heart Association, Inc.
Original Articles |
Sleep Modulates Hypertension in Leptin-Deficient Obese Mice
From the Department of Human and General Physiology, University of Bologna, Bologna, Italy.
Correspondence to Giovanna Zoccoli, Department of Human and General Physiology, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy. E-mail giovanna.zoccoli{at}unibo.it
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Leptin increases sympathetic activity, possibly contributing to hypertension in obese subjects. Hypertension increases cardiovascular mortality, with nighttime (sleep) blood pressure having a substantial prognostic value. We measured blood pressure in male leptin-deficient obese mice (ob/ob; n=7) and their lean wild-type littermates (+/+; n=11) during wakefulness, non–rapid-eye-movement sleep, and rapid-eye-movement sleep to investigate whether, in the absence of leptin, derangements of blood pressure are still associated with obesity and depend on the wake-sleep state. Mice were implanted with a telemetric pressure transducer and electrodes for discriminating wake-sleep states. Mean blood pressure was significantly higher in ob/ob than in +/+ mice during wakefulness (7.3±2.6 mm Hg) and non–rapid-eye-movement sleep (6.7±2.8 mm Hg) but not during rapid-eye-movement sleep (2.6±2.6 mm Hg). In ob/ob and +/+ mice, mean blood pressure was substantially higher during wakefulness than during non–rapid-eye-movement sleep. On passing from non–rapid-eye-movement sleep to rapid-eye-movement sleep, mean blood pressure decreased significantly in ob/ob but not in +/+ mice. The time spent during wakefulness was lower in ob/ob than in +/+ mice during the dark (active) period, whereas the opposite occurred during the light (rest) period. Consequently, mean blood pressure was significantly higher in ob/ob than in +/+ mice during the light (8.2±2.4 mm Hg) but not during the dark (3.0±2.9 mm Hg) period. These data suggest that, in the absence of leptin, obesity may entail hypertensive derangements of blood pressure, which are substantially modulated by the cardiovascular effects of the wake-sleep states.
Key Words: arterial pressure • behavior • heart rate • hypertension • obesity • investigative techniques • mice
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Obesity is a threat to health care because it is rapidly increasing in prevalence1 and is associated with hypertension and cardiovascular risk.2 The hormone leptin signals the abundance of fat stores and acts on the hypothalamus to mount adaptive adjustments of energy balance.3 Leptin also increases sympathetic activity and blood pressure (BP).4–6 Diet-induced obesity entails hyperleptinemia and resistance to the anorectic but not to the cardiovascular effects of leptin,7 which may, thus, contribute to obesity-related hypertension.8,9
Mutations that cause a lack of leptin or leptin receptors cause morbid obesity,3 allowing us to disentangle the cardiovascular correlates of obesity from those of hyperleptinemia. Although values of BP in the hypertensive range have been reported in obese subjects with congenital leptin deficiency,10 evidence of hypertension is not consistent in this rare form of obesity.11 Evidence is inconsistent also on obese mice with congenital impairment of leptin signaling, in which either hypotensive12–14 or hypertensive15–17 derangements of BP have been reported. In these mice, the occurrence15 or severity17 of hypertension vary between the light and dark periods, which entail different amounts of sleep time in mice.18 These observations are intriguing given the recent demonstration of a marked alteration of sleep structure in obese mice with congenital impairment of leptin signaling.19,20 Moreover, the observed hypertensive derangements in these mice15,17 are similar in magnitude to the physiological sleep-dependent changes in BP in mice.21,22 In particular, on passing from wakefulness (W) to non–rapid-eye-movement sleep (NREMS), BP substantially decreases in mice,21 similar to what occurs in human subjects.23 This decrease in BP is because of peripheral sympathetic withdrawal23,24 and cardiac vagal activation.25 On the other hand, rapid-eye-movement sleep (REMS) entails a dramatic repatterning of sympathetic activity26 and variable changes in cardiac output.27 On passing from NREMS to REMS, an increase in BP occurs in human subjects,23 whereas either increases or decreases in BP are observed in different inbred mouse strains.22
These considerations suggest that the cardiovascular effects of the wake-sleep states are a neglected yet potentially relevant source of variability in the derangements of BP, which are associated with obesity in the absence of leptin signaling. By performing simultaneous long-term recordings of BP and sleep, we directly tested the hypothesis that derangements of BP are modulated by the cardiovascular effects of wake-sleep states in leptin-deficient obese mice.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Experiments were performed on male mice homozygous for a nonsense mutation in the leptin gene (ob/ob) and on their littermates with 2 functional leptin alleles (+/+). For a detailed description of the materials and methods of this study, please see the online data supplement (available at http://hyper.ahajournals.org).
Surgical Procedures
Mice underwent surgery under general anesthesia and sterile conditions for the implantation of a telemetric BP transducer (TA11PA-C10, DSI), with the catheter inserted through the right femoral artery into the abdominal aorta,28 and of electrodes to obtain electroencephalographic and electromyographic signals.
Experimental Protocol
After a 4-day period of recovery from surgery and a subsequent 7-day period of habituation to the recording apparatus, BP, electroencephalography, electromyography, and activity were simultaneously and continuously measured on mice undisturbed and freely moving in their own cages. The BP signal was transmitted via telemetry. The telemetry system also yielded the activity signal by quantifying the spatial shifts of the implanted BP transducer. The electroencephalographic and electromyographic signals were transmitted via cable. At the end of recordings, mice were aged 15.0±0.5 weeks.
Data Analysis
A visual scoring of the wake-sleep states was performed on all of the consecutive 4-s epochs based on raw electroencephalographic and electromyographic recordings (Figure S1).18 Beat-to-beat values of systolic BP, diastolic BP, mean BP, and heart period were computed from the raw BP signal in each artifact-free 4-s epoch. For each mouse, these values were averaged within consecutive 1-hour periods, within light and dark periods, or within each wake-sleep state for the purpose of different analyses. Overall, the analysis was performed on 185.6, 245.2, and 33.8 hours of artifact-free recordings during W, NREMS, and REMS in ob/ob mice and on 283.7, 308.2, and 49.0 hours of artifact-free recordings during W, NREMS, and REMS in +/+ mice.
Statistical Analysis
Data were analyzed by ANOVA and t tests, with P<0.05 considered to be statistically significant. Data are reported as means ± SEMs in the text and the Figure, with n=7 for ob/ob mice and n=11 for +/+ mice.
|
; n=7) and +/+ mice (
; n=11). ANOVA: light-dark period: P<0.001 for all variables; mouse strain: P=0.018 (W), P=0.009 (NREMS), P=0.828 (REMS), P=0.047 (MBP); light-dark periodxmouse strain interaction: P<0.001 (W, NREMS, MBP), P=0.002 (REMS). *P<0.05 vs ob/ob mice (same light-dark period); 
P<0.05 vs dark period (same mouse strain). |
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Ob/ob mice were extremely obese, weighing approximately twice as much as +/+ mice (48.6±0.8 versus 25.5±0.7 g; P<0.001), and showed severely reduced activity levels during W with respect to +/+ mice (2.2±0.3 versus 6.3±0.7 arbitrary units; P<0.001).
The Table shows values of BP and heart period in ob/ob and +/+ mice as functions of the wake-sleep state. During W, ob/ob mice had higher values of mean BP (P=0.013) and diastolic BP (P=0.021) than +/+ mice. During NREMS, both mean BP (P=0.030) and diastolic BP (P=0.025) were also higher in ob/ob mice than in +/+ mice. Neither diastolic BP (P=0.136) nor mean BP (P=0.335) differed significantly between ob/ob and +/+ mice during REMS. Systolic BP did not differ significantly between ob/ob and +/+ mice in any wake-sleep state (P>0.114). In both mouse strains, systolic, diastolic, and mean BPs were substantially higher in W than in NREMS (P<0.001). On passing from NREMS to REMS, however, systolic, diastolic, and mean BPs decreased in ob/ob mice (P=0.039, P=0.025, and P=0.029, respectively), whereas they did not change significantly in +/+ mice (P>0.092). Heart period differed significantly among wake-sleep states (P<0.001), increasing on passing from W to NREMS and decreasing on passing from NREMS to REMS (P<0.001). Neither the statexstrain interaction effect (P=0.066) nor the main effect of the mouse strain (P=0.452) on heart period was statistically significant.
|
The Figure shows the 24-hour profiles of mean BP and of the time spent in each wake-sleep state. During the light period, ob/ob mice had higher mean BP (P=0.003) than +/+ mice and spent slightly more time during W (P=0.038) and correspondingly less time during REMS (P=0.045) with respect to +/+ mice. During the dark period, ob/ob mice spent less time during W (P=0.001) and more time during NREMS (P=0.001) and REMS (P=0.005) with respect to +/+ mice, whereas mean BP did not differ significantly between strains (P=0.320).
The 24-hour profiles of systolic and diastolic BPs were similar to that of mean BP and are shown in Figure S2, together with the 24-hour profile of the heart period. During the light period, ob/ob mice had higher diastolic BP (P<0.001) but similar values of systolic BP (P=0.086) and heart period (P=0.117) with respect to +/+ mice. During the dark period, diastolic BP (P=0.192), systolic BP (P=0.941), and heart period (P=0.552) did not differ significantly between ob/ob and +/+ mice.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this study, we showed that hypertensive derangements of BP occurred in leptin-deficient obese mice and were substantially modulated by the cardiovascular effects of the wake-sleep states. In ob/ob mice, we found increases in diastolic BP and mean BP with respect to +/+ mice (Table). Previous studies on BP in ob/ob mice yielded contrasting results, evidencing hypotension,12,13 no significant differences in BP,29,30 or hypertension limited to the light period15 with respect to lean control mice. These discrepancies bear no apparent relationship with the age, gender, and genetic background of the ob/ob mice that were studied. This is exemplified by the fact that hypertension in ob/ob mice was evidenced by the only study15 that measured BP by telemetry after prolonged postoperative recovery, as we did, regardless of differences between the mice investigated by that study15 (ie, female ob/ob mice aged 8 weeks from Jackson Laboratories) and ours (ie, male ob/ob mice aged 15 weeks from Harlan). Although telemetry is rightly considered a technique at the state of the art to measure BP in conscious freely moving mice,31 the discrepancies on BP control in obese mice lacking leptin signaling cannot be simply explained based on its adoption. In particular, obese db/db mice lacking functional leptin receptors have been reported as either hypotensive14 or hypertensive17 by using telemetry and as hypertensive by using the indirect tail-cuff method of BP measurement.16 Furthermore, although our experimental procedures were designed to minimize stress to the mice under study, we cannot exclude that ob/ob mice were more susceptible than +/+ mice to increases in BP induced by the surgical stress. A parsimonious explanation of the inconsistencies on the control of BP in ob/ob mice may, thus, be that, independent of leptin, obesity in these mice entails a fragility of BP control, with a proven potential for sustained hypertensive derangements. In this last respect, it should be noted that our finding of hypertension in ob/ob mice was based on the analysis of >1100 hours of BP recordings (see Methods section).
Combined recordings of sleep and BP have been successfully performed in few studies on mice.21,22,32 To our knowledge, our study was the first to apply this technique in a mouse model of human disease. Ob/ob mice were hypertensive with respect to +/+ mice during W and NREMS but not during REMS (Table). This occurred because, on passing from NREMS to REMS, BP significantly decreased in ob/ob mice, whereas BP did not differ significantly in +/+ mice. During REMS, central autonomic commands induce vasoconstriction in the skeletal muscles23 and vasodilatation of the mesenteric and renal vascular beds,26 the effect of these changes on BP being buffered by sino-aortic reflexes.27 The complexity of these factors generates the potential for interaction effects, whereby differences in BP on passing from NREMS to REMS reflect genetic22 and possibly also pathological derangements in cardiovascular regulation.
In agreement with previous studies,15,19 the differences in mean BP and those in the time spent in each wake-sleep state between ob/ob and +/+ mice depended on the light-dark period (Figure). At variance with previous studies,15,19 we simultaneously measured the 24-hour profile of BP and those of wake-sleep states in ob/ob mice (Figure) and combined this information with the analysis of the BP values in each given wake-sleep state (Table). We could, thus, demonstrate that the difference in mean BP between ob/ob and +/+ mice was reduced and became nonsignificant during the dark (active) period because ob/ob mice spent a lower fraction of this period awake with respect to +/+ mice. During the light (rest) period, conversely, the fact that ob/ob mice spent more time awake and correspondingly less time in REMS than +/+ mice slightly enhanced their difference in BP with respect to +/+ mice (Figure). The differences in BP between W and either NREMS or REMS were in fact substantial both in ob/ob and +/+ mice (Table) and comparable in magnitude with the average nightly decline of systolic BP in normal human subjects.33
Taken together, these observations indicate that sleep-dependent changes in BP buffered hypertension during REMS (Table) and the dark period (Figure) in ob/ob mice. Data, thus, supported our hypothesis that cardiovascular effects of the wake-sleep states are a relevant source of variability in the derangements of BP, which are associated with obesity in the absence of leptin signaling. This hypothesis fits well with recent findings that, in obese db/db mice lacking functional leptin receptors, the dark (active) period entails both an increase in the amount of NREMS time20 and a reduced severity of hypertension17 with respect to lean control mice. Nonetheless, our data remain preliminary, and additional studies to extend our findings are needed. In particular, systematic simultaneous recordings of sleep and BP are needed to determine whether sleep also modulates the hypotensive BP derangements, which may occur in ob/ob12,13 and db/db14 mice.
The increase in the amount of NREMS time during the dark (active) period, which we and others19,20 observed in obese mice with congenital impairment of leptin signaling, also occurs in mice with diet-induced obesity and functional leptin alleles.34 Intriguingly, excessive daytime sleepiness frequently occurs in obese human subjects even in the absence of sleep apnea, which is a potential causative factor.35 Obesity in human subjects is clearly associated with self-reported short sleep duration36 but not with objective polysomnographic measurements of sleep duration, indicating that self-reported short sleep may largely be a marker of emotional stress and subjective sleep disturbances in obese human subjects.37 Thus, both the nature of the link between obesity and sleep and its invariance among species remain unclear. On the other hand, sleep-dependent cardiovascular changes including the decrease in BP21,23,27,38 and the increased role of the baroreflex in cardiac control38–40 during NREMS are highly conserved across species, supporting the potential for extrapolation of our results. In this respect, our finding that obesity, per se (ie, in the absence of leptin), entailed increases in mean BP, which were prominent during the light (rest) period and also occurred during NREMS, may be of particular relevance. In rats with 2-kidney, 1-clip hypertension that were subjected to different regimens of captopril treatment, the best predictor of cardiac hypertrophy was BP during the light (rest) period.41 In patients referred for ambulatory BP monitoring, nighttime (sleep) BP significantly predicted total mortality,42 as well as cardiovascular mortality, even after adjusting for daytime (waking) BP values.43 It is worth noting that increases in BP with magnitudes similar to those that we observed in ob/ob mice are associated with substantial increases in cardiovascular risk in human subjects.44 In obese human subjects, BP is higher than in lean controls not only during the day but also during the night.45 Although obstructive sleep apneas may contribute to the increase in BP during sleep in obesity,46 they are unlikely to explain the increase in BP observed during NREMS in ob/ob mice, which have a depressed chemosensitivity to carbon dioxide but no evidence of upper airway obstruction during sleep.47
Perspectives
The results of our study suggest that, in the absence of leptin, obesity may entail hypertensive derangements of BP. Because such derangements manifest not only during W but also during NREMS, they may have substantial relevance for cardiovascular health. Our study also demonstrates the value of teasing out W, NREMS, and REMS when investigating BP derangements, the magnitude of which is comparable to that of the physiological sleep-dependent changes in BP. This approach may be particularly useful in preclinical research when the genetic mutation under study is known or suspected to alter sleep structure.
|
Acknowledgments |
|---|
Sources of Funding
This work has been funded by the University of Bologna (RFO 06 and Strategic Project 2006) and by the Fondazione Cassa di Risparmio di Bologna (grant 100, May 27, 2007).
Disclosures
None.
Received October 23, 2008; first decision November 8, 2008; accepted December 4, 2008.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology. 2007; 132: 2087–2102.[CrossRef][Medline] [Order article via Infotrieve]
2. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. An update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006; 113: 898–918.
3. Barsh GS, Farooqi S, O'Rahilly S. Genetics of body weight regulation. Nature. 2000; 404: 644–651.[Medline] [Order article via Infotrieve]
4. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997; 100: 270–278.[Medline] [Order article via Infotrieve]
5. Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 1998; 31: 409–414.
6. Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, Matsuoka N, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y, Nakao K. Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest. 2000; 105: 1243–1252.[Medline] [Order article via Infotrieve]
7. Rahmouni K, Morgan DA, Morgan GM, Mark AL, Haynes WG. Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes. 2005; 54: 2012–2018.
8. Rahmouni K, Correia ML, Haynes WG, Mark AL. Obesity-associated hypertension: new insights into mechanisms. Hypertension. 2005; 45: 9–14.
9. Koh KK, Park SM, Quon MJ. Leptin and cardiovascular disease: response to therapeutic interventions. Circulation. 2008; 117: 3238–3249.
10. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998; 18: 213–215.[CrossRef][Medline] [Order article via Infotrieve]
11. Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab. 1999; 84: 3686–3695.
12. Mark AL, Shaffer RA, Correia ML, Morgan DA, Sigmund CD, Haynes WG. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens. 1999; 17: 1949–1953.[CrossRef][Medline] [Order article via Infotrieve]
13. Christoffersen C, Bollano E, Lindegaard ML, Bartels ED, Goetze JP, Andersen CB, Nielsen LB. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology. 2003; 144: 3483–3490.[CrossRef][Medline] [Order article via Infotrieve]
14. Bodary PF, Shen Y, Ohman M, Bahrou KL, Vargas FB, Cudney SS, Wickenheiser KJ, Myers MGJ, Eitzman DT. Leptin regulates neointima formation after arterial injury through mechanisms independent of blood pressure and the leptin receptor/STAT3 signaling pathways involved in energy balance. Arterioscler Thromb Vasc Biol. 2007; 27: 70–76.
15. Swoap SJ. Altered leptin signaling is sufficient, but not required, for hypotension associated with caloric restriction. Am J Physiol (Heart Circ Physiol). 2001; 281: H2473–H2479.
16. Bagi Z, Erdei N, Toth A, Li W, Hintze TH, Koller A, Kaley G. Type 2 diabetic mice have increased arteriolar tone and blood pressure: enhanced release of COX-2-derived constrictor prostaglandins. Arterioscler Thromb Vasc Biol. 2005; 25: 1610–1616.
17. Su W, Guo Z, Randall DC, Cassis L, Brown DR, Gong MC. Hypertension and disrupted blood pressure circadian rhythm in type 2 diabetic db/db mice. Am J Physiol (Heart Circ Physiol). 2008; 295: H1634–H1641.
18. Franken P, Malafosse A, Tafti M Genetic determinants of sleep regulation in inbred mice. Sleep. 1999; 155–169.
19. Laposky AD, Shelton J, Bass J, Dugovic C, Perrino N, Turek FW. Altered sleep regulation in leptin-deficient mice. Am J Physiol (Regul Integr Comp Physiol). 2006; 290: R894–R903.
20. Laposky AD, Bradley MA, Williams DL, Bass J, Turek FW. Sleep-wake regulation is altered in leptin resistant (db/db) genetically obese and diabetic mice. Am J Physiol (Regul Integr Comp Physiol). 2008; 295: R2059–R2066.
21. Schaub CD, Tankersley C, Schwartz AR, Smith PL, Robotham JL, O'Donnell CP. Effect of sleep/wake state on arterial blood pressure in genetically identical mice. J Appl Physiol. 1998; 85: 366–371.
22. Campen MJ, Tagaito Y, Jenkins TP, Smith PL, Schwartz AR, O'Donnel CP. Phenotypic differences in the hemodynamic response during REM sleep in six strains of inbred mice. Physiol Genomics. 2002; 11: 227–234.
23. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med. 1993; 328: 303–307.
24. Miki K, Kato M, Kajii S. Relationship between renal sympathetic nerve activity and arterial pressure during REM sleep in rats. Am J Physiol (Regul Integr Comp Physiol). 2003; 284: R467–R473.
25. Baust W, Bohnert B. The regulation of heart rate during sleep. Exp Brain Res. 1969; 7: 169–180.[Medline] [Order article via Infotrieve]
26. Mancia G, Baccelli G, Adams DB, Zanchetti A. Vasomotor regulation during sleep in the cat. Am J Physiol. 1971; 220: 1086–1093.
27. Silvani A. Physiological sleep-dependent changes in arterial blood pressure: central autonomic commands and baroreflex control. Clin Exp Pharmacol Physiol. 2008; 35: 987–994.[Medline] [Order article via Infotrieve]
28. Tank J, Jordan J, Diedrich A, Obst M, Plehm R, Luft FC, Gross V. Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation. Hypertension. 2004; 43: 1042–1047.
29. Barouch LA, Berkowitz DE, Harrison RW, O'Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003; 108: 754–759.
30. Dong F, Zhang X, Yang X, Esberg LB, Yang H, Zhang Z, Culver B, Ren J. Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice. J Endocrinol. 2006; 188: 25–36.
31. Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE. Recommendations for blood pressure measurement in humans and experimental animals part 2: blood pressure measurement in experimental animals. A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005; 45: 299–310.
32. Sakata M, Sei H, Eguchi N, Morita Y, Urade Y. Arterial pressure and heart rate increase during REM sleep in adenosine A2A-receptor knockout mice, but not in wild-type mice. Neuropsychopharmacology. 2005; 30: 1856–1860.[CrossRef][Medline] [Order article via Infotrieve]
33. Staessen JA, Bieniaszewski L, O'Brien E, Gosse P, Hayashi H, Imai Y, Kawasaki T, Otsuka K, Palatini P, Thijs L, Fagard R. Nocturnal blood pressure fall on ambulatory monitoring in a large international database. Hypertension. 1997; 29: 30–39.
34. Guan Z, Vgontzas AN, Bixler EO, Fang J. Sleep is increased by weight gain and decreased by weight loss in mice. Sleep. 2008; 31: 627–633.[Medline] [Order article via Infotrieve]
35. Vgontzas AN, Bixler EO, Tan T-L, Kantner D, Martin LF, Kales A. Obesity without sleep apnea is associated with daytime sleepiness. Arch Intern Med. 1998; 158: 1333–1337.
36. Cappuccio FP, Taggart FM, Kandala NB, Currie A, Peile E, Stranges S, Miller MA. Meta-analysis of short sleep duration and obesity in children and adults. Sleep. 2008; 31: 619–626.[Medline] [Order article via Infotrieve]
37. Vgontzas AN, Lin HM, Papaliaga M, Calhoun S, Vela-Bueno A, Chrousos GP, Bixler EO. Short sleep duration and obesity: the role of emotional stress and sleep disturbances. Int J Obes (Lond). 2008; 32: 801–809.[CrossRef][Medline] [Order article via Infotrieve]
38. Berteotti C, Asti V, Ferrari V, Franzini C, Lenzi P, Zoccoli G, Silvani A. Central and baroreflex control of heart period during the wake-sleep cycle in spontaneously hypertensive rats. Am J Physiol (Regul Integr Comp Physiol). 2007; 293: R293–R298.
39. Silvani A, Asti V, Bojic T, Ferrari V, Franzini C, Lenzi P, Grant DA, Walker AM, Zoccoli G. Sleep-dependent changes in the coupling between heart period and arterial pressure in newborn lambs. Pediatr Res. 2005; 57: 108–114.[CrossRef][Medline] [Order article via Infotrieve]
40. Silvani A, Grimaldi D, Vandi S, Barletta G, Vetrugno R, Provini F, Pierangeli G, Berteotti C, Montagna P, Zoccoli G, Cortelli P. Sleep-dependent changes in the coupling between heart period and blood pressure in human subjects. Am J Physiol (Regul Integr Comp Physiol). 2008; 294: R1686–R1692.
41. Morgan TO, Brunner HR, Aubert JF, Wang Q, Griffiths C, Delbridge L. Cardiac hypertrophy depends upon sleep blood pressure: a study in rats. J Hypertens. 2000; 18: 445–451.[CrossRef][Medline] [Order article via Infotrieve]
42. Ben-Dov IZ, Kark JD, Ben-Ishay D, Mekler J, Ben-Arie L, Bursztyn M. Predictors of all-cause mortality in clinical ambulatory monitoring. Unique aspects of blood pressure during sleep. Hypertension. 2007; 49: 1235–1241.
43. Boggia J, Li Y, Thijs L, Hansen TW, Kikuya M, Bjorklund-Bodegård K, Richart T, Ohkubo T, Kuznetsova T, Torp-Pedersen C, Lind L, Ibsen H, Imai Y, Wang J, Sandoya E, O'Brien E, Staessen JA. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet. 2007; 370: 1219–1229.[CrossRef][Medline] [Order article via Infotrieve]
44. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002; 360: 1903–1913.[CrossRef][Medline] [Order article via Infotrieve]
45. Kotsis V, Stabouli S, Bouldin M, Low A, Toumanidis S, Zakopoulos N. Impact of obesity on 24-hour ambulatory blood pressure and hypertension. Hypertension. 2005; 45: 602–607.
46. Davies CW, Crosby JH, Mullins RL, Barbour C, Davies RJ, Stradling JR. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. Thorax. 2000; 55: 736–740.
47. O'Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, Smith PL. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med. 1999; 159: 1477–1484.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||