Glen E. Foster

Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea

Obstructive sleep apnoea (OSA) has been implicated as a risk factor for the development of hypertension, stroke and myocardial infarction. The main cause of cardiovascular and cerebrovascular disease in OSA is thought to be exposure to intermittent hypoxia, which can lead to oxidative stress, inflammation, atherosclerosis, endothelial dysfunction and hypertension. These proposed mechanisms have been drawn from basic research in animal and human models of intermittent hypoxia in addition to clinical investigation of patients with OSA. This review outlines the association between OSA and vascular disease, describes basic mechanisms that may be responsible for this association and compares the results from studies of OSA subjects with those in experimental models of intermittent hypoxia.

Effects of Exposure to Intermittent Hypoxia on Oxidative Stress and Acute Hypoxic Ventilatory Response in Humans

RATIONALE Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans. OBJECTIVES To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR. METHODS After two normoxic control days (Day -4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1-4) of intermittent hypoxia for 6 hours per day. MEASUREMENTS AND MAIN RESULTS AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring alpha-tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and alpha-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002). CONCLUSIONS Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.

Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia

We determined the ventilatory, cardiovascular and cerebral tissue oxygen response to two protocols of normobaric, isocapnic, intermittent hypoxia. Subjects (n= 18, male) were randomly assigned to short‐duration intermittent hypoxia (SDIH, 12% O2 separated by 5 min of normoxia for 1 h) or long‐duration intermittent hypoxia (LDIH, 30 min of 12% O2). Both groups had 10 exposures over a 12 day period. The hypoxic ventilatory response (HVR) was measured before each daily intermittent hypoxia exposure on days 1, 3, 5, 8, 10 and 12. The HVR was measured again 3 and 5 days after the end of intermittent hypoxia. During all procedures, ventilation, blood pressure, heart rate, arterial oxyhaemoglobin saturation and cerebral tissue oxygen saturation were measured. The HVR increased throughout intermittent hypoxia exposure regardless of protocol, and returned to baseline by day 17 (day 1, 0.84 ± 0.50; day 12, 1.20 ± 1.01; day 17, 0.95 ± 0.58 l min−1%SaO2−1; P < 0.01). The change in systolic blood pressure sensitivity (r=+0.68; P < 0.05) and the change in diastolic blood pressure sensitivity (r=+0.73; P < 0.05) were related to the change in HVR, while the change in heart rate sensitivity was not (r=+0.32; NS). The change in cerebral tissue oxygen saturation sensitivity to hypoxia was less on day 12, and returned to baseline by day 17 (day 1, −0.51 ± 0.13; day 12, −0.64 ± 0.18; day 17, −0.51 ± 0.13; P < 0.001). Acute exposure to SDIH increased mean arterial pressure (+5 mmHg; P < 0.01), but LDIH did not (P > 0.05). SDIH and LDIH had similar effects on the ventilatory and cardiovascular response to acute progressive hypoxia and hindered cerebral oxygenation. Our findings indicate that the vascular processes required to control blood flow and oxygen supply to cerebral tissue in a healthy human are hindered following exposure to 12 days of isocapnic intermittent hypoxia.

Cardiovascular and cerebrovascular responses to acute hypoxia following exposure to intermittent hypoxia in healthy humans

Intermittent hypoxia (IH) is thought to be responsible for many of the long‐term cardiovascular consequences associated with obstructive sleep apnoea (OSA). Experimental human models of IH can aid in investigating the pathophysiology of these cardiovascular complications. The purpose of this study was to determine the effects of IH on the cardiovascular and cerebrovascular response to acute hypoxia and hypercapnia in an experimental human model that simulates the hypoxaemia experienced by OSA patients. We exposed 10 healthy, male subjects to IH for 4 consecutive days. The IH profile involved 2 min of hypoxia (nadir = 45.0 mmHg) alternating with 2 min of normoxia (peak = 88.0 mmHg) for 6 h. The cerebral blood flow response and the pressor responses to hypoxia and hypercapnia were assessed after 2 days of sham exposure, after each day of IH, and 4 days following the discontinuation of IH. Nitric oxide derivatives were measured at baseline and following the last exposure to IH. After 4 days of IH, mean arterial pressure increased by 4 mmHg (P < 0.01), nitric oxide derivatives were reduced by 55% (P < 0.05), the pressor response to acute hypoxia increased (P < 0.01), and the cerebral vascular resistance response to hypoxia increased (P < 0.01). IH alters blood pressure and cerebrovascular regulation, which is likely to contribute to the pathogenesis of cardiovascular and cerebrovascular disease in patients with OSA.

Sex Differences in Respiratory Exercise Physiology

Respiratory exercise physiology research has historically focused on male subjects. In the last 20 years, important physiological and functional differences have been noted between the male and female response to dynamic exercise where sex differences have been reported for most of the major determinants of exercise capacity. Female participation in competitive and recreational sport is growing worldwide and it is universally accepted that participation in regular physical activity is of health benefit for both sexes. Understanding sex differences is of potential importance to both the clinician-scientist and the exercise physiologist since differences could impact upon exercise rehabilitation programmes for patient populations, exercise prescription for disease prevention in healthy individuals and training strategies for competitive athletes. Sex differences have been shown in resting pulmonary function, which may impact on the respiratory response to exercise. Women typically have smaller lung volumes and maximal expiratory flow rates even when corrected for height relative to men. Differences in resting and exercising ventilation across the menstrual cycle and relative to men have also been reported, although the functional significance remains unclear. Expiratory flow limitation and a high work of breathing are seen in women. Pulmonary system limitations, in particular exercise-induced arterial hypoxia, have been reported in both men and women; however, the prevalence in women is not yet known. From the available literature, it appears that there are sex differences in some areas of respiratory exercise physiology. However, detailed sex comparisons are difficult because the number of subjects studied to date has been woefully small.

Acute hypoxic ventilatory response and exercise-induced arterial hypoxemia in men and women

Recent studies claim a higher prevalence of exercise-induced arterial hypoxemia (EIAH) in women relative to men and that diminished peripheral chemosensitivity is related to the degree of arterial desaturation during exercise in male endurance athletes. The purpose of this study was to determine the relationship between the acute ventilatory response to hypoxia (AHVR) and EIAH and the potential influence of gender in trained endurance cyclists and untrained individuals. Healthy untrained males (n = 9) and females (n = 9) and trained male (n = 11) and female (n = 10) cyclists performed an isocapnic AHVR test followed by an incremental cycle test to exhaustion. Oxyhemoglobin saturation (Sa(O(2)) was lower in trained men (91.4 +/- 0.9%) and women (91.3 +/- 0.9%) compared to their untrained counterparts (94.4 +/- 0.8% versus 94.3 +/- 0.7%) (P < 0.05). AHVR and maximal O(2) consumption were related for all subjects (r = -0.46), men (r = -0.45) and women (r = -0.53) (P < 0.05) but AHVR was unrelated to Sa(O(2)) for any groups (P > 0.05). We conclude that resting AHVR does not have a significant role in maintaining Sa(O(2)) during sea-level maximal cycle exercise in men or women.

Oxygen cost of exercise hyperpnoea is greater in women compared with men

The oxygen cost of breathing represents a significant fraction of total oxygen uptake during intense exercise. At a given ventilation, women have a greater work of breathing compared with men, and because work is linearly related to oxygen uptake we hypothesized that their oxygen cost of breathing would also be greater. For a given ventilation, women had a greater absolute oxygen cost of breathing, and this represented a greater fraction of total oxygen uptake. Regardless of sex, those who developed expiratory flow limitation had a greater oxygen cost of breathing at maximal exercise. The greater oxygen cost of breathing in women indicates that a greater fraction of total oxygen uptake (and possibly cardiac output) is directed to the respiratory muscles, which may influence blood flow distribution during exercise.

Losartan abolishes oxidative stress induced by intermittent hypoxia in humans

Non‐Technical Summary  Intermittent hypoxia is known to increase oxidative stress and decrease nitric oxide metabolism. These two responses, which are involved in hypoxia‐induced hypertension, may be mediated by angiotensin II. Using a novel human experimental model, we show that blockade of the type 1 angiotensin II receptors by a medication called losartan prevented the increase in oxidative stress and the decrease in nitric oxide metabolism induced by 6 h of intermittent hypoxia. These results show that the upregulation of angiotensin II contributes to the overproduction of free radicals associated with intermittent hypoxia and help us better understand why blood pressure increases in medical disorders associated with intermittent hypoxia, such as obstructive sleep apnoea.

Exercise‐induced arterial hypoxaemia and the mechanics of breathing in healthy young women

•  By virtue of their smaller lung volumes and airway diameters, women develop more mechanical ventilatory constraints during exercise, which may result in increased vulnerability to hypoxaemia during exercise. •  Hypoxaemia developed at all exercise intensities with varying patterns and was more common in aerobically trained subjects; however, some untrained women also developed hypoxaemia. •  Mechanical respiratory constraints directly lead to hypoxaemia in some women and prevent adequate reversal of hypoxaemia in most women. •  Experimentally reversing mechanical constraints with heliox gas partially reversed the hypoxaemia in subjects who developed expiratory flow limitation. •  Due in part to increased mechanical ventilatory constraints, the respiratory systems response to exercise is less than ideal in most women.

Ventilatory and cerebrovascular responses to hypercapnia in patients with obstructive sleep apnoea: effect of CPAP therapy.

The purpose of this study was to assess whether the cerebrovascular response to hypercapnia is blunted in OSA patients and if this could alter the ventilatory response to hypercapnia before and after CPAP therapy. We measured the cerebrovascular, cardiovascular and ventilatory responses to hypercapnia in 8 patients with OSA (apnoea-hypopnoea index=101+/-10) before and after 4-6 weeks of CPAP therapy and in 10 control subjects who did not undergo CPAP therapy. The cerebrovascular and ventilatory responses to hypercapnia were not different between OSA and controls at baseline or follow-up. The cardiovascular response to hypercapnia was significantly increased in the OSA group by CPAP therapy (mean arterial pressure response: 1.30+/-0.16 vs. 2.04+/-0.36 mmHg Torr(-1); p=0.007). We conclude that in normocapnic, normotensive OSA patients without cardiovascular disease, the ventilatory, cerebrovascular, and cardiovascular responses to hypercapnia are normal, but the cardiovascular response to hypercapnia is heightened following 1 month of CPAP therapy.