Clinical trial NCT02058823: Intermittent Hypoxia 2: Cardiovascular and Metabolism
Official title: Cardiovascular and Metabolic Physiological Adaptations to Intermittent Hypoxia. Physiological Aspects and Expression of Receptors and Cellular Mediators
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Hypoxia
Sleep Apnea
Obstructive Sleep Apnea
Keywords: Hypoxia
Sleep apnea
Valsartan
Amlodipine
Healthy subjects
Randomized
Cross-over
International
Sympathetic nervous system
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2014-02-10
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in sympathetic activity
timeFrame: Day 1 and at Day 14
Secondary outcomes:
measure: Measure of adrenergic, inflammatory and metabolic markers in adipose tissues by chronic intermittent hypoxia versus placebo in healthy nonobese subjects.
timeFrame: Day 14
measure: Measure variations in parameters of inflammation in adipose tissue by chronic intermittent hypoxia versus placebo in healthy nonobese subjects.
timeFrame: Day 14
measure: Measure of metabolic aspects of the OGTT test.
timeFrame: Day 14
measure: 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.
timeFrame: Day 14
measure: Assessing markers implicated in the pathophysiology of chronic metabolic diseases after HI versus placebo in healthy nonobese subjects during OGTT.
timeFrame: Day 14
measure: Change in vascular responsivness
timeFrame: At day 1 and Day 14
measure: Change in Sympathetic and vascular determinant of Blood pressure
timeFrame: Day 1 and Day 14
Other outcomes:
Locations:
city: La Tronche
country: France
facility: Laboratoire EFCR - Functional Cardio-respiratory Exploration Laboratory
state: Isère
Study officials:
affiliation: University Hospital of Genoble
name: Renaud RT Tamisier, PhD
role: PRINCIPAL_INVESTIGATOR
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