Intermittent Hypoxia-hyperoxia Conditioning as a New Therapeutic Intervention to Reduce Hypertension (HyperIHHC)

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.