Intermittent Hypoxia 2: Cardiovascular and Metabolism

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Cardiovascular and Metabolic Physiological Adaptations to Intermittent Hypoxia. Physiological Aspects and Expression of Receptors and Cellular Mediators

Conditions
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Hypoxia, Sleep Apnea, Obstructive Sleep Apnea

Intervention / Treatment
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* Drug: Placebo
* Drug: Placebo
* Drug: Valsartan
* Drug: Amlodipine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subject Subject aged of 18 years-old at least Diagnostic AHI<15/h and <5% of total sleep time spent with a SaO2<90% Free and informed consent signed Subject covered by social security Negative pregnancy test Exclusion Criteria: Subject with a medical pathology (respiratory, cardiovascular, renal, metabolic, neurological...) Tobacco consumption > 5 cigarettes/days Alcohol consumption > 3 units/days (1 unit=1 drink) Subject under trusteeship or guardianship Subject unaffiliated with the social security Person deprived of their liberty, adult protected by laws, person hospitalized Ongoing participation in another clinical research study Subject non-cooperative or respectful of obligations inherent in the participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm 1: Real hypoxia and ¨Placebo<br>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. | Drug: Placebo<br>* The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all.<br>* Other names: Placebo Valsartan;|
| Placebo Comparator: Arm 2: Hypoxia placebo and Placebo<br>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. | Drug: Placebo<br>* The subjects receive 1 oral pill of placebo each morning during the second week of the two periods, so 14 pills in all.<br>* Other names: Placebo Almodipine;|
| Active Comparator: Arm 3: Hypoxia and Valsartan<br>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. | Drug: Valsartan<br>* 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.<br>* Other names: Tareg;|
| Active Comparator: Arm 4: Hypoxia and Amlodipine<br>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. | Drug: Amlodipine<br>* 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.<br>* Other names: Effective Amlodipine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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. | Non-stress: by measuring the cytokines pro-and anti-inflammatory (IL-1, IL-6, IL-4, IL-10, IL-12, RANTES, TNF, leptin, adiponectin, CD68). OGTT: Kinetics concentrations of C-reactive protein, TNF-α, IL6, IL8, IL1-ß, CCL2/MCP-1, PAI-1, IL-1 Ra, IL-10. | Day 14 | 
| Assessing markers implicated in the pathophysiology of chronic metabolic diseases after HI versus placebo in healthy nonobese subjects during OGTT. | Psychology:Hunger, appetite and food preference by validated questionnaires. Behavior:Calorie intake, food choices, energy expenditure. Physiology: Metabolism rest:Indirect calorimetry. Carbohydrate metabolism:Glucose tolerance, sensitivity to insulin, insulin secretion, time profiles of several proteins. Neuroendocrine control of appetite:Temporal Patterns of hormones. Lipid profiles:Temporal Patterns of FFA, concentrations of triglycerides and cholesterol. Autonomic nervous system activity:Cardiac inter-beat intervals, urine sample, time profiles of catecholamines. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxia, Sleep apnea, Valsartan, Amlodipine, Healthy subjects, Randomized, Cross-over, International, Sympathetic nervous system