Clinical trial NCT05603676: Intermittent Hypoxia-hyperoxia Conditioning as a New Therapeutic Intervention to Reduce Hypertension (HyperIHHC)
Official title: Intermittent Hypoxia-hyperoxia Conditioning as a New Therapeutic Intervention to Reduce Hypertension
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hypertension
Keywords: Intermittent hypoxia-hyperoxia conditioning
Vascular function
Hemorheology
Lead sponsor: University of Lausanne
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Universitaire Vaudois
First posted: 2022-11-03
Enrollment: 72
Sex: ALL
Minimum age (years): 44
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This project is a single center national study. It is designed as a randomized single-blinded parallel group control study. Single-blinded means that participants will not be inform than a half will follow a placebo intervention. Parallel group means that the design serves to compare different experimental conditions. Randomized means that the participants are assigned to the two different conditions randomly (by chance alone). Control means that one of the group/conditions is the standard of comparison (control participant achieving placebo and IHHC interventions). A follow-up, one month after the intervention will be done.
Primary purpose: TREATMENT

Brief summary: The primary objective of this project is to examine the efficiency of intermittent hypoxia-hyperoxia conditioning (IHHC) protocol to improve vascular health and reduce blood pressure in hypertensive patients (stage 1). The result of the present study will investigate if IHHC could be a therapeutic treatment for hypertensive individuals. The investigation is designed with a placebo intervention (air ambient) and a control group (age-matched healthy participants). The interest of short cycles of intermittent hypoxia-hyperoxia is due to the triggering of the vasodilatory response in a greater extent compared to the pressor mechanisms since the exposure duration remains short. Therefore, it can be hypothesized that control and hypertensive groups achieving IHHC may exhibit a decreased blood pressure compared to the control and hypertensive groups achieving placebo intervention. The control group may show greater change than hypertensive due to higher vascular reserve.

The secondary objective of the study is to understand the underlying mechanism of the beneficial effects of IHHC, especially the role of blood hemorheological changes. Based on available literature, it is know that hypoxia induce an increase in blood viscosity. One may hypothesize that with such a short hypoxic dose used during IHHC, only minor change in blood viscosity may occur. However, a slight rise in blood viscosity is known to stimulate NO synthase and then to produce more NO. Hence it could be one of the mechanisms involved in the early vasodilatory response to hypoxia. These findings are in line with the reported higher NO end-product metabolites during exercise in normoxia and hypoxia in subjects who showed a rise in blood viscosity after exercise. The hypothesis is that the magnitude of IHHC beneficial effects is related to change in blood viscosity and its determinants.

Detailed description: The prevalence and absolute burden of hypertension is rising worldwide and represents one of the leading modifiable risk factors for cardiovascular diseases being indirectly involved in the development of, for instance, stroke, kidney diseases, and dementia.

There is rather solid evidence supporting the assumption that intermittent and continuous hypoxia at rest or in combination with exercise is generally effective to reduce blood pressure and positively influence vascular health.

A well-designed and controlled hypoxic stimulus may induce benefits for health and is known as hypoxia conditioning (HC). Indeed, brief and repeated exposures to hypoxia trigger cellular and systemic physiological adaptations that make the organism more resilient to subsequent severe hypoxic stress, and possibly also to other stressors.

The mechanisms associated with an antihypertensive effect of moderate hypoxia may include vascular adaptions (e.g. increased vascularisation and endothelium-dependent vasodilatation) as well as adaptations in the autonomic nervous system (e.g. reduced sympathetic activity).

Hypoxia exposure leads to a multiphasic blood flow and pressure response over time. The first and immediate phase following hypoxic stimulus is characterized by a systemic vasodilation that aims to counteract the decrease in arterial oxygen (O2) content and subsequent peripheral O2 delivery. If hypoxia exposure lasts for more than few minutes, pressor mechanisms, such as sympathetic activation, a rise in arterial stiffness, an increase in endothelin-1 levels, a baroreflex dysfunction and an elevation in blood viscosity, exceed vasodilatory responses resulting in a rise of blood pressure. However, the mechanisms at the onset of the early blood pressure response are beneficial for vascular health and an improvement in vascular function following intermittent hypoxia exposure has been reported during both intermittent resting exposure (FiO2: 10-14%, 3-5 minutes of normobaric hypoxia per cycle, 3-25 cycles/day during 10 to 30 days \[7\]) or intermittent exposure combined with exercise (2 hrs of hypobaric hypoxic exposure (FiO2: 16.5%) with 30 minutes of moderate intensity exercise, 4 days/week during 8 weeks).

This is likely related to the release of vasodilatory molecules, mainly nitric oxide (NO), and the activation of transcriptional factors, such as hypoxia inducible factor (HIF-1) and nuclear factor erythroid-2 related factor 2 (Nrf2), which are beneficial for vascular function through the enhanced production/activity of vascular endothelial growth factor, erythropoietin, and antioxidant enzymes. However, it was reported that severe hypoxia (FiO2 = 12%) but not moderate hypoxia (FiO2 = 15%) (1 h/day, 5 days/week for 4 weeks) impaired endothelial function \[19\] suggesting that vascular benefits from hypoxia are a matter of dose.

Cardiovascular disorders are associated with poor vascular function, increased arterial stiffness or impaired endothelial and non-endothelial flow-mediated dilation. Although less investigated, blood flow properties also play a key role in the development and progression of vascular disorders and dysfunction. More particularly, the viscosity of blood has a major impact on regulating vascular function. One of the most famous hematological adaptations following chronic hypoxia exposure is the increase in total hemoglobin mass, generally associated to the elevation in hematocrit (Hct), which may enhance the oxygen-carrying capacity. However, Hct is also a major determinant of blood viscosity, and any elevation in blood viscosity may have consequences on vascular resistance and blood perfusion, particularly in the absence of compensatory mechanisms. Hence, in order to understand the benefits of hypoxia exposure on vascular health, the related changes in blood viscosity must be considered. Unfortunately, studies on hypoxia conditioning and vascular functions usually do not measure the change in blood viscosity, which remains a forgotten factor for the understanding of hypoxia-related improvement/impairment of vascular function.

An innovative strategy of conditioning is to interspersed hypoxia exposure trial with hyperoxic one, since the latter also stimulate HIF-1 and Nfr2 pathway, and is called intermittent hypoxia/hyperoxia conditioning (IHHC). Three studies have found that IHHC can decrease systolic (- 2.9% to - 13.9%) and diastolic blood pressure (- 9.0% to 14.0%), although the changes did not always reach statistical significance (p=0.07). With regard to studies using intermittent hypoxia/normoxia, young males with stage I hypertension were exposed to 20 consecutive days of intermittent hypoxic exposure (4-10 cycles per session, 3 min of hypoxia \[ FiO2 = 10%\] interspersed by 3 min of normoxia). A decrease of 22 mmHg in systolic and 16.6 mmHg in diastolic blood pressure was reported after exposure. A decreases of 10-30 mmHg in systolic and 10-15 mmHg in diastolic blood pressure in patients with stage I to II hypertension after intermittent or prolonged hypoxic exposure was also reported. Recent meta-analysis have shown that every reduction of 10 mmHg in systolic or 5 mmHg in diastolic blood pressure reduced the risk of major cardiovascular events by 20%, the genesis of cardiovascular diseases by 17-40%, and all-cause mortality by 13%. Indeed, a decrease of even 2 mmHg in systolic blood pressure would involve a 10% lower stroke mortality and about 7% lower mortality for cardiovascular heart diseases or other vascular causes in middle age. Given the evidence that IHHC can trigger a reduction in systolic and diastolic blood pressure in patients with and without cardiovascular diseases, it can be considered as a promising therapeutic strategy to reduce systemic blood pressure. Therefore, the hypotensive effect of IHHC is practically relevant to prevent the genesis or exacerbation of cardiovascular diseases and ensure a healthy life.

The primary objective of this project is to examine the efficiency of IHHC protocol to improve vascular health and reduce blood pressure in hypertensive patients (stage 1). The result of the present study will investigate if IHHC could be a therapeutic treatment for hypertensive individuals. The investigation is designed with a placebo intervention (air ambient) and a control group (age-matched healthy participants). The interest of short cycles of intermittent hypoxia-hyperoxia is due to the triggering of the vasodilatory response in a greater extent compared to the pressor mechanisms since the exposure duration remains short. Therefore, it can be hypothesized that control and hypertensive groups achieving IHHC may exhibit a decreased blood pressure compared to the control and hypertensive groups achieving placebo intervention. The control group may show greater change than hypertensive due to higher vascular reserve.

The secondary objective of the study is to understand the underlying mechanism of the beneficial effects of IHHC, especially the role of blood hemorheological changes. Based on available literature, it is know that hypoxia induce an increase in blood viscosity. One may hypothesize that with such a short hypoxic dose used during IHHC, only minor change in blood viscosity may occur. However, a slight rise in blood viscosity is known to stimulate NO synthase and then to produce more NO. Hence it could be one of the mechanisms involved in the early vasodilatory response to hypoxia. These findings are in line with the reported higher NO end-product metabolites during exercise in normoxia and hypoxia in subjects who showed a rise in blood viscosity after exercise. The hypothesis is that the magnitude of IHHC beneficial effects is related to change in blood viscosity and its determinants.

Eligibility criteria: Inclusion Criteria:

1. to be aged between 44 and 65 years old.
2. for women, post-menopausal will be considered.
3. for hypertensive group, stage 1 hypertension: systolic blood pressure (140-159 mmHg) and/or diastolic blood pressure (90-99 mmHg).
4. free of other disease than hypertension and free of anti-hypertensive treatment medication.
5. Hypertensive participants with 14 days of hypertensive drugs wash-out.
6. able to complete all sessions.
7. able to give consent.

Exclusion Criteria:

1. Peripheral arterial disease
2. Atrial fibrillation
3. Hypoxic congenital heart diseases
4. Pulmonary Hypertension
5. using dietary supplements or drugs which interfere with the measurements (nitrate supplementation)

Primary outcomes:
measure: 24 hours Blood pressure change form pre to post intervention
timeFrame: One week before the intervention and one week after the intervention
Secondary outcomes:
measure: Baroreflex sensitivity
timeFrame: One week before the intervention and one week after the intervention
measure: Reactive hyperemia index
timeFrame: One week before the intervention and one week after the intervention
measure: Vascular occlusion test (VOT)
timeFrame: One week before the intervention and one week after the intervention
measure: Pulse wave velocity
timeFrame: One week before the intervention and one week after the intervention
measure: Cerebrovascular reactivity to carbon dioxide (CO2)
timeFrame: One week before the intervention and one week after the intervention
measure: Advanced oxidation protein products
timeFrame: One week before the intervention and one week after the intervention
measure: Malondialdehyde
timeFrame: One week before the intervention and one week after the intervention
measure: Superoxide dismutase
timeFrame: One week before the intervention and one week after the intervention
measure: Glutathion peroxydase
timeFrame: One week before the intervention and one week after the intervention
measure: Catalase
timeFrame: One week before the intervention and one week after the intervention
measure: Nitric oxide end products
timeFrame: One week before the intervention and one week after the intervention
measure: Blood viscosity (cp)
timeFrame: One week before the intervention and one week after the intervention
measure: Blood volume
timeFrame: One week before the intervention and one week after the intervention
measure: Plasma viscosity (cp)
timeFrame: One week before the intervention and one week after the intervention
measure: Hematocrit
timeFrame: One week before the intervention and one week after the intervention
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: ISSUL
state: VD
Study officials:
affiliation: University of Lausanne
name: Grégoire P Millet, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lyamina NP, Lyamina SV, Senchiknin VN, Mallet RT, Downey HF, Manukhina EB. Normobaric hypoxia conditioning reduces blood pressure and normalizes nitric oxide synthesis in patients with arterial hypertension. J Hypertens. 2011 Nov;29(11):2265-72. doi: 10.1097/HJH.0b013e32834b5846.
citation: Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016 Mar 5;387(10022):957-967. doi: 10.1016/S0140-6736(15)01225-8. Epub 2015 Dec 24.
citation: Serebrovskaya TV, Xi L. Intermittent hypoxia training as non-pharmacologic therapy for cardiovascular diseases: Practical analysis on methods and equipment. Exp Biol Med (Maywood). 2016 Sep;241(15):1708-23. doi: 10.1177/1535370216657614. Epub 2016 Jul 12.