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| ID | Type | Description | Link |
|---|---|---|---|
| P-2011-32-HI2 | Other Identifier | CPP Caen |
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budget constraints
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| Name | Class |
|---|---|
| Institut National de la Santé Et de la Recherche Médicale, France | OTHER_GOV |
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The purpose of this study is to compare cardiovascular physiological adaptation to intermittent hypoxia (IH) of nonobese healthy subjects. The exposure will be two periods of two weeks (IH versus exposure "placebo hypoxia"). The investigators will use pharmacological tools, peripheral vasodilator (amlodipine) or specific blocker of angiotensin receptor (valsartan) versus the taking of a placebo. The allocation of the tool and the exhibition will be randomized (HI / placebo, valsartan / amlodipine). The outcome measures evaluated concern the cardiovascular system, systemic inflammation and tissular and glucose metabolism.
The investigators assume an increase in arterial resistance during the intermittent hypoxia compared to the control group, these being dependent on sympathetic tone.
The investigators hypothesize that the metabolic alterations that will be observed after experimental simulation (IH and fragmentation of sleep for 15 consecutive nights) will be less severe in the valsartan group than in the amlodipine group in comparison with the placebo group.
A serum bank and a gene bank will be performed for the requirements of subsequent studies if necessary.
There are many physiological situations in which the organism is exposed to hypoxia, such as exercise and altitude. In addition some pathological situations also involve hypoxia, such as obesity, heart failure, respiratory failure and sleep apnea syndrome.
Hypoxia associated with altitude is frequently marked by the presence of sleep during periodic breathing induces a particular pattern of hypoxia called intermittent hypoxia. Also some subjects are "intolerant altitude" and develop specific pathologies at high altitude (acute mountain evil, pulmonary edema ...).
We recently demonstrated that subjects tolerate the altitude had just intermittent hypoxia while they were sleeping during the simulated altitude. The protective role of intermittent hypoxia in the mechanisms of occurrence of intolerance to altitude remains to be understood more precisely. In fact those who were intolerant to altitude has no periodic breathing and therefore intermittent hypoxia during the oxygen-deficient atmosphere.
Conversely, the sleep apnea syndrome (SAS) also characterized by a HI. It is produced by repeated episodes of airway obstruction during sleep, producing a sequence: respiratory effort, hypoxia / re-oxygenation and sleep interruption.
The HI is associated with both a well established cardiovascular morbidity but also to cardioprotection. This relates to cardiovascular morbidity rise in blood pressure can certainly promote the development after many years of hypertension. On the other hand the presence of sleep apnea syndrome is advanced as a factor favoring the coronary collateral circulation and therefore will bring a cardioprotective effect for patients.
Understanding the mechanisms of physiological adaptations to intermittent hypoxia by passing a deleterious evolution of a protective HI is therefore critical.
Exposure to altitude or OSAS induces the activation of intermediary mechanisms such as sympathetic activation, altered vascular reactivity, systemic inflammation and low-grade oxidative stress. The direct involvement of these mechanisms is dependent mainly intermediate of intermittent hypoxia. The shift in equilibrium between activator and inhibitor factors will evolve either to a protective mode (adaptation to altitude) or pathologic (cardiovascular complication of OSA).
Sympathetic activation has been demonstrated in patients with OSAS, reversible with effective treatment. The importance of cardiovascular sympathetic activation in elevating blood pressure by intermittent hypoxia is shown in animal models of HI. We also found an increase in sympathetic activation in our reversible model of HI in healthy subjects.
The elevation of that sympathetic activity is assumed to be multifactorial. An increase in tone but also a central potentiation thereof by an increase in peripheral chemoreflex sensitivity (sensitive to hypoxia) and against a lack of regulation by the arterial baroreflex.
Moreover angiotensin system modulates the central sympathetic tone and peripheral chemoreflex sensitivity. These actions are complementary in a signaling pathway of particular interest in exposure to intermittent hypoxia.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1: Real hypoxia and ¨Placebo | Placebo Comparator | This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the real hypoxia and the placebo during the first two weeks and, after the wash-out, receive the treatment of the arm 2. |
|
| Arm 2: Hypoxia placebo and Placebo | Placebo Comparator | This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the hypoxia placebo and the placebo during the first two weeks and, after the wash-out, receive the treatment of the arm 1. |
|
| Arm 3: Hypoxia and Valsartan | Active Comparator | This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the real hypoxia and the Valsartan during the first two weeks and, after the wash-out, receive the treatment of the arm 4. |
|
| Arm 4: Hypoxia and Amlodipine | Active Comparator | This arm last 4 weeks with 2 periods of 2 weeks separated by a 6 weeks wash-out. The subjects of this arm receive the real hypoxia and the amlodipine during the first two weeks and, after the wash-out, receive the treatment of the arm 3. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in sympathetic activity | The sympathetic activity will be directly measured by microneurography of the peroneal nerve | Day 1 and at Day 14 |
| Measure | Description | Time Frame |
|---|---|---|
| Measure of adrenergic, inflammatory and metabolic markers in adipose tissues by chronic intermittent hypoxia versus placebo in healthy nonobese subjects. | The adrenergic receptors will be evaluated by immuno histochemistry appearance and by measuring mRNA levels of alpha and beta and AT1 and AT2 receptors by RT-PCR on total RNA extracted from the subcutaneous adipose tissue. Insulin sensitivity test would be performed on adipose tissues. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Renaud RT Tamisier, PhD | University Hospital of Genoble | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Laboratoire EFCR - Functional Cardio-respiratory Exploration Laboratory | La Tronche | Isère | 38700 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19858231 | Background | Steiner S, Schueller PO, Schulze V, Strauer BE. Occurrence of coronary collateral vessels in patients with sleep apnea and total coronary occlusion. Chest. 2010 Mar;137(3):516-20. doi: 10.1378/chest.09-1136. Epub 2009 Oct 26. | |
| 12586529 | Background | Lavie L. Obstructive sleep apnoea syndrome--an oxidative stress disorder. Sleep Med Rev. 2003 Feb;7(1):35-51. doi: 10.1053/smrv.2002.0261. |
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| ID | Term |
|---|---|
| D000860 | Hypoxia |
| D012891 | Sleep Apnea Syndromes |
| D020181 | Sleep Apnea, Obstructive |
| ID | Term |
|---|---|
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001049 | Apnea |
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| ID | Term |
|---|---|
| D000068756 | Valsartan |
| D017311 | Amlodipine |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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|
| Placebo | Drug | The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all. |
|
|
| Valsartan | Drug | The subjects receive 1 oral pill of Valsartan each morning during the second week of the two periods, so 14 pills in all. 1 pill equal 40 mg. |
|
|
| Amlodipine | Drug | The subjects receive 1 oral pill of Amlodipine each morning during the second week of the two periods, so 14 pills in all. 1 pill equal 6,944 mg of amlodipine besilate with 5 mg of amlodipine. |
|
|
| Day 14 |
| Measure variations in parameters of inflammation in adipose tissue by chronic intermittent hypoxia versus placebo in healthy nonobese subjects. | The inflammation will be assessed by measuring mRNA levels of proinflammatory cytokines and anti-inflammatory (IL-1, IL-6, IL-4, IL-10, IL-12, RANTES, TNF, leptin, adiponectin, CD68 (macrophage inflammation)) by RT-PCR on total RNA extracted (Mirvana, Ambion) from the subcutaneous adipose tissue. | Day 14 |
| Measure of metabolic aspects of the OGTT test. | Measure of glucose intolerance and insulin sensitivity inducing by intermittent hypoxia by multisamples OGTT test. | Day 14 |
| Measure the activation of systemic inflammation by chronic HI versus placebo in healthy nonobese subjects. The systemic inflammation will be assessed in non-stress and during the OGTT. |
| Day 14 |
| Assessing markers implicated in the pathophysiology of chronic metabolic diseases after HI versus placebo in healthy nonobese subjects during OGTT. |
| Day 14 |
| Change in vascular responsivness | Some others vascular beds will be explored skin, eyes before and after intermittent hypoxia.Use o f a laser doppler cutaneous, choroidal and ophthalmic arteries. | At day 1 and Day 14 |
| Change in Sympathetic and vascular determinant of Blood pressure | Heart rate variability and vascular flow and arterial pressure. Heart rate variability will be measure from 24h ECG recording.The vascular flow will be measured by Doppler waveform of the popliteal artery. The blood pressure will be measured by an ambulatory blood pressure monitoring. | Day 1 and Day 14 |
| 14532320 | Background | Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA. 2003 Oct 8;290(14):1906-14. doi: 10.1001/jama.290.14.1906. |
| 8404098 | Background | Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest. 1993 Jun;103(6):1763-8. doi: 10.1378/chest.103.6.1763. |
| 7560081 | Background | Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995 Oct;96(4):1897-904. doi: 10.1172/JCI118235. |
| 7758555 | Background | Hedner J, Darpo B, Ejnell H, Carlson J, Caidahl K. Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J. 1995 Feb;8(2):222-9. doi: 10.1183/09031936.95.08020222. |
| 1428112 | Background | Fletcher EC, Lesske J, Culman J, Miller CC, Unger T. Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension. 1992 Nov;20(5):612-9. doi: 10.1161/01.hyp.20.5.612. |
| 20525723 | Background | Tamisier R, Pepin JL, Remy J, Baguet JP, Taylor JA, Weiss JW, Levy P. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J. 2011 Jan;37(1):119-28. doi: 10.1183/09031936.00204209. Epub 2010 Jun 4. |
| 9529260 | Background | Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation. 1998 Mar 17;97(10):943-5. doi: 10.1161/01.cir.97.10.943. |
| 8912770 | Background | Carlson JT, Hedner JA, Sellgren J, Elam M, Wallin BG. Depressed baroreflex sensitivity in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 1996 Nov;154(5):1490-6. doi: 10.1164/ajrccm.154.5.8912770. |
| 19011148 | Background | Punjabi NM, Beamer BA. Alterations in Glucose Disposal in Sleep-disordered Breathing. Am J Respir Crit Care Med. 2009 Feb 1;179(3):235-40. doi: 10.1164/rccm.200809-1392OC. Epub 2008 Nov 14. |
| 19444258 | Background | Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol. 2009 May;5(5):253-61. doi: 10.1038/nrendo.2009.23. |
| 9350634 | Background | Larsen JJ, Hansen JM, Olsen NV, Galbo H, Dela F. The effect of altitude hypoxia on glucose homeostasis in men. J Physiol. 1997 Oct 1;504 ( Pt 1)(Pt 1):241-9. doi: 10.1111/j.1469-7793.1997.241bf.x. |
| 11457773 | Background | Braun B, Rock PB, Zamudio S, Wolfel GE, Mazzeo RS, Muza SR, Fulco CS, Moore LG, Butterfield GE. Women at altitude: short-term exposure to hypoxia and/or alpha(1)-adrenergic blockade reduces insulin sensitivity. J Appl Physiol (1985). 2001 Aug;91(2):623-31. doi: 10.1152/jappl.2001.91.2.623. |
| 16227462 | Background | Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol (1985). 2005 Nov;99(5):2008-19. doi: 10.1152/japplphysiol.00660.2005. |
| 10956244 | Background | Spiegel K, Leproult R, Colecchia EF, L'Hermite-Baleriaux M, Nie Z, Copinschi G, Van Cauter E. Adaptation of the 24-h growth hormone profile to a state of sleep debt. Am J Physiol Regul Integr Comp Physiol. 2000 Sep;279(3):R874-83. doi: 10.1152/ajpregu.2000.279.3.R874. |
| 15531540 | Background | Spiegel K, Leproult R, L'hermite-Baleriaux M, Copinschi G, Penev PD, Van Cauter E. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab. 2004 Nov;89(11):5762-71. doi: 10.1210/jc.2004-1003. |
| 10543671 | Background | Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999 Oct 23;354(9188):1435-9. doi: 10.1016/S0140-6736(99)01376-8. |
| 19228987 | Background | Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas R, Levy P, Weiss JW. A new model of chronic intermittent hypoxia in humans: effect on ventilation, sleep, and blood pressure. J Appl Physiol (1985). 2009 Jul;107(1):17-24. doi: 10.1152/japplphysiol.91165.2008. Epub 2009 Feb 19. |
| 20581089 | Background | Gilmartin GS, Lynch M, Tamisier R, Weiss JW. Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H925-31. doi: 10.1152/ajpheart.00253.2009. Epub 2010 Jun 25. |
| 21045724 | Background | Bilo G, Caldara G, Styczkiewicz K, Revera M, Lombardi C, Giglio A, Zambon A, Corrao G, Faini A, Valentini M, Mancia G, Parati G. Effects of selective and nonselective beta-blockade on 24-h ambulatory blood pressure under hypobaric hypoxia at altitude. J Hypertens. 2011 Feb;29(2):380-7. doi: 10.1097/HJH.0b013e3283409014. |
| 18539753 | Background | Gilmartin GS, Tamisier R, Curley M, Weiss JW. Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans. Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H778-85. doi: 10.1152/ajpheart.00653.2007. Epub 2008 Jun 6. |
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| 17873026 | Background | Tamisier R, Hunt BE, Gilmartin GS, Curley M, Anand A, Weiss JW. Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy humans. Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H3027-35. doi: 10.1152/ajpheart.00277.2007. Epub 2007 Sep 14. |
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| 10500042 | Background | Roche F, Gaspoz JM, Court-Fortune I, Minini P, Pichot V, Duverney D, Costes F, Lacour JR, Barthelemy JC. Screening of obstructive sleep apnea syndrome by heart rate variability analysis. Circulation. 1999 Sep 28;100(13):1411-5. doi: 10.1161/01.cir.100.13.1411. |
| 15583226 | Background | Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004 Dec 7;141(11):846-50. doi: 10.7326/0003-4819-141-11-200412070-00008. |
| 18172212 | Background | Tasali E, Leproult R, Ehrmann DA, Van Cauter E. Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1044-9. doi: 10.1073/pnas.0706446105. Epub 2008 Jan 2. |
| 11950155 | Background | Hoppeler H, Vogt M. Hypoxia training for sea-level performance. Training high-living low. Adv Exp Med Biol. 2001;502:61-73. doi: 10.1007/978-1-4757-3401-0_6. |
| 18725495 | Background | Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Russell R, Woo M, Young T; American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology; American Heart Association Stroke Council; American Heart Association Council on Cardiovascular Nursing; American College of Cardiology Foundation. Sleep apnea and cardiovascular disease: an American Heart Association/american College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation. 2008 Sep 2;118(10):1080-111. doi: 10.1161/CIRCULATIONAHA.107.189375. Epub 2008 Aug 25. No abstract available. |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
| D020919 | Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
| D014633 |
| Valine |
| D000597 | Amino Acids, Branched-Chain |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000601 | Amino Acids, Essential |
| D004095 | Dihydropyridines |
| D011725 | Pyridines |