Krishna M. Sundar, MD, FCCP

Clinicians are well aware of the acute effects of hypoxemia when encountered in conditions such as pulmonary embolism, pulmonary edema, COPD exacerbation, and others, whereas effects of chronic hypoxemia, such as pulmonary hypertension and polycythemia, are more difficult to recognize. Chronic hypoxemia is frequent in chronic lung diseases, such as COPD, but how it leads to increased mortality in severe COPD is unknown (NHLBI Working Group for LTOT in COPD. Am J Respir Crit Care Med. 2006;174:373). Chronic hypoxemia following high altitude exposure tends to have more unpredictable effects. Chronic hypoxemia, greater than that expected for the altitude of residence, is encountered frequently in high altitude dwellers. Here it has been implicated in the pathophysiology of chronic mountain sickness (Villafeurte and Corante. High Alt Med Biol. 2016;17[2]:61) and low birth weights (Maatta J, et al. Sci Rep. 2018;8[1]:13583), even though high altitude residence has been linked to better cardiovascular outcomes and reduced cancer-related deaths (Burstcher M. Aging Dis. 2013;5[4]:274). Chronic hypoxia effects at high altitude may, therefore, be variegated depending on a number of factors that include organ-system-specific effects, severity of chronic hypoxia, and a propensity to disease determined by genetic background and generations of residence.

Such diverse effects of chronic sleep-related hypoxemia are also being reported with obstructive sleep apnea (OSA). While sleep can result in sustained drops in ventilation and consequent hypoxemia similar to what is seen in COPD, OSA is typified by a form of sleep-related hypoxemia in a pattern termed as chronic intermittent hypoxia (CIH). CIH is characterized by rapid fluctuations in oxygen saturations (Figure 1) that is virtually pathognomonic of sleep apnea either from recurrent upper airway obstructions (as in OSA) or pauses in respiratory generator firing (as in central sleep apnea). OSA-driven CIH has received most attention, given its purported role in in the causation of the wide range of pathologic conditions associated with OSA. Outcomes from cross-sectional and longitudinal studies have correlated time spent below 90% or recurrent oxygen desaturations to a number of OSA-related outcomes such as cardiovascular disease, diabetes, and cognitive dysfunction (Dewan et al. Chest. 2015;147[1]:266). While these effects of OSA-related intermittent hypoxemia occur over long periods of time, as with other forms of chronic hypoxia, some effects, such as hypertension, are demonstrable in animal models after much shorter durations of sleep-related intermittent hypoxia exposure. As seen with other forms of chronic hypoxemia, an opposing beneficial effect has also been demonstrated on the size of myocardial infarct during acute coronary events and from mild OSA-related mortality in elderly subjects (Javaheri et al. J Am Coll Cardiol. 2017;69[7]:841).

Given how common sleep-related hypoxemia and OSA are, it is important to understand the implications of different patterns of sleep-related hypoxemia that a vast segment of the population experiences on a nightly basis. A number of factors may determine chronic outcomes with sleep-related hypoxemia that include the pattern of sleep-related hypoxemia (chronic sustained hypoxemia associated with sleep-related hypoventilation vs chronic intermittent hypoxemia of OSA), degree of hypoxemia, presence of underlying disease, and hitherto undescribed individual factors. While a correlation between hypoxemic burden secondary to sleep-disordered breathing and cardiovascular outcomes has been shown (Azabarzin A, et al. Eur Heart J. 2018 Oct 30), CPAP interventional studies that address OSA-related CIH have shown mixed results for prevention of cardiovascular disease (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919). It has also been difficult to draw upon results of oxygen supplementation in other forms of hypoxemia, such as COPD, when specifically targeted to addressing the hypoxemia seen only at night or with exercise (LOTT Research Group. N Engl J Med. 2016;375:1617 ). To complicate this further, high altitude residence (that may result in similar levels of sleep-related hypoxemia) is not associated with any differences in life-expectancy but may provide a reduction in cardiovascular outcomes (Ezzati, et al. J Epidemiol Community Health. 2012;66[7]:e17).

How do we reconcile such disparate effects of chronic hypoxemia? Part of difference may be in the pattern of chronic intermittent hypoxemia noted with OSA characterized not only by rapid drops in oxygen but also rapid reoxygenation events secondary to arousals terminating an apnea – these reoxygenation events have been attributed to the increased oxidant stress demonstrable in multiple tissues. While chronic hypoxia itself may cause increased oxidant stress, such effects seen with sustained forms of hypoxia, such as sleep-related hypoventilation or high altitude residence, may be more gradual resulting in lesser degrees of tissue effects and regulation of antioxidant defenses with sustained exposure. Herein lies the importance of understanding physiologic and biological effects stemming from chronic hypoxia to explain its variegated effects on different organ systems. In this regard, the role of carotid body, a structure with unique vascular supply and with the ability to respond to minor changes in oxygen saturation as is seen in patients with OSA is key to the causation of hypertension associated with OSA (Shell et al. Curr Hyperten Rep. 2016;18[3]:19). Carotid body activation by intermittent hypoxia and long-term sensory facilitation drives the elevated sympathetic activity and consequent increases in blood pressure that can be improved by supplemental oxygen (Turnbull CD, et al. Am J Respir Crit Care Med. 2019;199[2]:211).

While carotid body responses are key to the pathophysiology of OSA, every organ in the body (in fact, every cell within the body) has the ability to sense and respond to hypoxia. This ability to sense oxygen tensions is ingrained in every cell by virtue of oxygen’s critical role in the genesis of life and evolution. These cellular responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), isoforms of which include the more ubiquitous HIF-1 found in all parenchymal cells and HIF-2 found in specialized erythropoietin-producing cells of the kidney and the pulmonary circulation (the polycythemia and pulmonary vasoconstrictive responses from hypoxia are mediated through HIF-2 ). HIFs mediate the transcription of hundreds of genes, and they have been implicated in the pathobiology of a wide range of phenomena, from cancer to atherosclerotic vascular disease, metabolic syndrome, neurodegenerative disorders, pulmonary hypertension, and nonalcoholic fatty liver disease (Prabhakar and Semenza. Physiol Rev. 2012;92[3]:967). While HIF activation is an attractive target for examining the effects of chronic hypoxia of high altitude and sleep-disordered breathing, HIF activation varies from tissue to tissue and interacts with a number of other cellular systems in leading to differential effects. The short half-life of HIF proteins make them difficult to detect in tissues, so a number of secondary HIF-effects has been measured with mixed results depending on animal model utilized, pattern and degree of hypoxia studied, and the target effect measured. Comparative effects of intermittent vs sustained hypoxemia need to be systematically studied in different organ systems in different species, given the differing oxygen thresholds of individual cells due to unique blood flows and variations in the system of co-factors and prolyl hydroxylases that regulate the activation of HIFs. While the thrust of the work has been centered on HIF-related effects and the role of NF-kB-driven inflammation seen in OSA, there is substantial evidence to the role of oxidant stress that may be directly related to reoxygenation events occurring with CIH (Lavie L. Sleep Med Rev. 2015;20:27).

For life that has been intricately involved with oxygen from its genesis, it is not unreasonable to expect adaptations of cells, organs, and the whole individual to a wide range of oxygen tensions. Attempts to understand the import of sleep-disordered breathing has led to a need to unravel the implications of OSA-related chronic intermittent hypoxia and sleep-hypoventilation. This has led to a resurgence of interest in hypoxia-related research. Whether such chronic sleep-related sustained and intermittent hypoxemia is a harbinger of chronic disease is still not fully clear. A number of challenges exist with the understanding of these chronic hypoxia effects that include the long time needed for disease occurrence, its differential effects on organ systems, the role of hypoxia vs reoxygenation injury, importance of local blood flow, etc. Understanding these pathways will be crucial in prognosticating the role of sleep-related hypoxemia, the recognition of which has become part and parcel of routine management in sleep medicine.

Dr. Sundar is Medical Director, Sleep-Wake Center, Clinical Professor, Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah.

Clinicians are well aware of the acute effects of hypoxemia when encountered in conditions such as pulmonary embolism, pulmonary edema, COPD exacerbation, and others, whereas effects of chronic hypoxemia, such as pulmonary hypertension and polycythemia, are more difficult to recognize. Chronic hypoxemia is frequent in chronic lung diseases, such as COPD, but how it leads to increased mortality in severe COPD is unknown (NHLBI Working Group for LTOT in COPD. Am J Respir Crit Care Med. 2006;174:373). Chronic hypoxemia following high altitude exposure tends to have more unpredictable effects. Chronic hypoxemia, greater than that expected for the altitude of residence, is encountered frequently in high altitude dwellers. Here it has been implicated in the pathophysiology of chronic mountain sickness (Villafeurte and Corante. High Alt Med Biol. 2016;17[2]:61) and low birth weights (Maatta J, et al. Sci Rep. 2018;8[1]:13583), even though high altitude residence has been linked to better cardiovascular outcomes and reduced cancer-related deaths (Burstcher M. Aging Dis. 2013;5[4]:274). Chronic hypoxia effects at high altitude may, therefore, be variegated depending on a number of factors that include organ-system-specific effects, severity of chronic hypoxia, and a propensity to disease determined by genetic background and generations of residence.

Such diverse effects of chronic sleep-related hypoxemia are also being reported with obstructive sleep apnea (OSA). While sleep can result in sustained drops in ventilation and consequent hypoxemia similar to what is seen in COPD, OSA is typified by a form of sleep-related hypoxemia in a pattern termed as chronic intermittent hypoxia (CIH). CIH is characterized by rapid fluctuations in oxygen saturations (Figure 1) that is virtually pathognomonic of sleep apnea either from recurrent upper airway obstructions (as in OSA) or pauses in respiratory generator firing (as in central sleep apnea). OSA-driven CIH has received most attention, given its purported role in in the causation of the wide range of pathologic conditions associated with OSA. Outcomes from cross-sectional and longitudinal studies have correlated time spent below 90% or recurrent oxygen desaturations to a number of OSA-related outcomes such as cardiovascular disease, diabetes, and cognitive dysfunction (Dewan et al. Chest. 2015;147[1]:266). While these effects of OSA-related intermittent hypoxemia occur over long periods of time, as with other forms of chronic hypoxia, some effects, such as hypertension, are demonstrable in animal models after much shorter durations of sleep-related intermittent hypoxia exposure. As seen with other forms of chronic hypoxemia, an opposing beneficial effect has also been demonstrated on the size of myocardial infarct during acute coronary events and from mild OSA-related mortality in elderly subjects (Javaheri et al. J Am Coll Cardiol. 2017;69[7]:841).

Given how common sleep-related hypoxemia and OSA are, it is important to understand the implications of different patterns of sleep-related hypoxemia that a vast segment of the population experiences on a nightly basis. A number of factors may determine chronic outcomes with sleep-related hypoxemia that include the pattern of sleep-related hypoxemia (chronic sustained hypoxemia associated with sleep-related hypoventilation vs chronic intermittent hypoxemia of OSA), degree of hypoxemia, presence of underlying disease, and hitherto undescribed individual factors. While a correlation between hypoxemic burden secondary to sleep-disordered breathing and cardiovascular outcomes has been shown (Azabarzin A, et al. Eur Heart J. 2018 Oct 30), CPAP interventional studies that address OSA-related CIH have shown mixed results for prevention of cardiovascular disease (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919). It has also been difficult to draw upon results of oxygen supplementation in other forms of hypoxemia, such as COPD, when specifically targeted to addressing the hypoxemia seen only at night or with exercise (LOTT Research Group. N Engl J Med. 2016;375:1617 ). To complicate this further, high altitude residence (that may result in similar levels of sleep-related hypoxemia) is not associated with any differences in life-expectancy but may provide a reduction in cardiovascular outcomes (Ezzati, et al. J Epidemiol Community Health. 2012;66[7]:e17).

How do we reconcile such disparate effects of chronic hypoxemia? Part of difference may be in the pattern of chronic intermittent hypoxemia noted with OSA characterized not only by rapid drops in oxygen but also rapid reoxygenation events secondary to arousals terminating an apnea – these reoxygenation events have been attributed to the increased oxidant stress demonstrable in multiple tissues. While chronic hypoxia itself may cause increased oxidant stress, such effects seen with sustained forms of hypoxia, such as sleep-related hypoventilation or high altitude residence, may be more gradual resulting in lesser degrees of tissue effects and regulation of antioxidant defenses with sustained exposure. Herein lies the importance of understanding physiologic and biological effects stemming from chronic hypoxia to explain its variegated effects on different organ systems. In this regard, the role of carotid body, a structure with unique vascular supply and with the ability to respond to minor changes in oxygen saturation as is seen in patients with OSA is key to the causation of hypertension associated with OSA (Shell et al. Curr Hyperten Rep. 2016;18[3]:19). Carotid body activation by intermittent hypoxia and long-term sensory facilitation drives the elevated sympathetic activity and consequent increases in blood pressure that can be improved by supplemental oxygen (Turnbull CD, et al. Am J Respir Crit Care Med. 2019;199[2]:211).

While carotid body responses are key to the pathophysiology of OSA, every organ in the body (in fact, every cell within the body) has the ability to sense and respond to hypoxia. This ability to sense oxygen tensions is ingrained in every cell by virtue of oxygen’s critical role in the genesis of life and evolution. These cellular responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), isoforms of which include the more ubiquitous HIF-1 found in all parenchymal cells and HIF-2 found in specialized erythropoietin-producing cells of the kidney and the pulmonary circulation (the polycythemia and pulmonary vasoconstrictive responses from hypoxia are mediated through HIF-2 ). HIFs mediate the transcription of hundreds of genes, and they have been implicated in the pathobiology of a wide range of phenomena, from cancer to atherosclerotic vascular disease, metabolic syndrome, neurodegenerative disorders, pulmonary hypertension, and nonalcoholic fatty liver disease (Prabhakar and Semenza. Physiol Rev. 2012;92[3]:967). While HIF activation is an attractive target for examining the effects of chronic hypoxia of high altitude and sleep-disordered breathing, HIF activation varies from tissue to tissue and interacts with a number of other cellular systems in leading to differential effects. The short half-life of HIF proteins make them difficult to detect in tissues, so a number of secondary HIF-effects has been measured with mixed results depending on animal model utilized, pattern and degree of hypoxia studied, and the target effect measured. Comparative effects of intermittent vs sustained hypoxemia need to be systematically studied in different organ systems in different species, given the differing oxygen thresholds of individual cells due to unique blood flows and variations in the system of co-factors and prolyl hydroxylases that regulate the activation of HIFs. While the thrust of the work has been centered on HIF-related effects and the role of NF-kB-driven inflammation seen in OSA, there is substantial evidence to the role of oxidant stress that may be directly related to reoxygenation events occurring with CIH (Lavie L. Sleep Med Rev. 2015;20:27).

For life that has been intricately involved with oxygen from its genesis, it is not unreasonable to expect adaptations of cells, organs, and the whole individual to a wide range of oxygen tensions. Attempts to understand the import of sleep-disordered breathing has led to a need to unravel the implications of OSA-related chronic intermittent hypoxia and sleep-hypoventilation. This has led to a resurgence of interest in hypoxia-related research. Whether such chronic sleep-related sustained and intermittent hypoxemia is a harbinger of chronic disease is still not fully clear. A number of challenges exist with the understanding of these chronic hypoxia effects that include the long time needed for disease occurrence, its differential effects on organ systems, the role of hypoxia vs reoxygenation injury, importance of local blood flow, etc. Understanding these pathways will be crucial in prognosticating the role of sleep-related hypoxemia, the recognition of which has become part and parcel of routine management in sleep medicine.

Dr. Sundar is Medical Director, Sleep-Wake Center, Clinical Professor, Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah.

Clinicians are well aware of the acute effects of hypoxemia when encountered in conditions such as pulmonary embolism, pulmonary edema, COPD exacerbation, and others, whereas effects of chronic hypoxemia, such as pulmonary hypertension and polycythemia, are more difficult to recognize. Chronic hypoxemia is frequent in chronic lung diseases, such as COPD, but how it leads to increased mortality in severe COPD is unknown (NHLBI Working Group for LTOT in COPD. Am J Respir Crit Care Med. 2006;174:373). Chronic hypoxemia following high altitude exposure tends to have more unpredictable effects. Chronic hypoxemia, greater than that expected for the altitude of residence, is encountered frequently in high altitude dwellers. Here it has been implicated in the pathophysiology of chronic mountain sickness (Villafeurte and Corante. High Alt Med Biol. 2016;17[2]:61) and low birth weights (Maatta J, et al. Sci Rep. 2018;8[1]:13583), even though high altitude residence has been linked to better cardiovascular outcomes and reduced cancer-related deaths (Burstcher M. Aging Dis. 2013;5[4]:274). Chronic hypoxia effects at high altitude may, therefore, be variegated depending on a number of factors that include organ-system-specific effects, severity of chronic hypoxia, and a propensity to disease determined by genetic background and generations of residence.

Such diverse effects of chronic sleep-related hypoxemia are also being reported with obstructive sleep apnea (OSA). While sleep can result in sustained drops in ventilation and consequent hypoxemia similar to what is seen in COPD, OSA is typified by a form of sleep-related hypoxemia in a pattern termed as chronic intermittent hypoxia (CIH). CIH is characterized by rapid fluctuations in oxygen saturations (Figure 1) that is virtually pathognomonic of sleep apnea either from recurrent upper airway obstructions (as in OSA) or pauses in respiratory generator firing (as in central sleep apnea). OSA-driven CIH has received most attention, given its purported role in in the causation of the wide range of pathologic conditions associated with OSA. Outcomes from cross-sectional and longitudinal studies have correlated time spent below 90% or recurrent oxygen desaturations to a number of OSA-related outcomes such as cardiovascular disease, diabetes, and cognitive dysfunction (Dewan et al. Chest. 2015;147[1]:266). While these effects of OSA-related intermittent hypoxemia occur over long periods of time, as with other forms of chronic hypoxia, some effects, such as hypertension, are demonstrable in animal models after much shorter durations of sleep-related intermittent hypoxia exposure. As seen with other forms of chronic hypoxemia, an opposing beneficial effect has also been demonstrated on the size of myocardial infarct during acute coronary events and from mild OSA-related mortality in elderly subjects (Javaheri et al. J Am Coll Cardiol. 2017;69[7]:841).

Given how common sleep-related hypoxemia and OSA are, it is important to understand the implications of different patterns of sleep-related hypoxemia that a vast segment of the population experiences on a nightly basis. A number of factors may determine chronic outcomes with sleep-related hypoxemia that include the pattern of sleep-related hypoxemia (chronic sustained hypoxemia associated with sleep-related hypoventilation vs chronic intermittent hypoxemia of OSA), degree of hypoxemia, presence of underlying disease, and hitherto undescribed individual factors. While a correlation between hypoxemic burden secondary to sleep-disordered breathing and cardiovascular outcomes has been shown (Azabarzin A, et al. Eur Heart J. 2018 Oct 30), CPAP interventional studies that address OSA-related CIH have shown mixed results for prevention of cardiovascular disease (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919). It has also been difficult to draw upon results of oxygen supplementation in other forms of hypoxemia, such as COPD, when specifically targeted to addressing the hypoxemia seen only at night or with exercise (LOTT Research Group. N Engl J Med. 2016;375:1617 ). To complicate this further, high altitude residence (that may result in similar levels of sleep-related hypoxemia) is not associated with any differences in life-expectancy but may provide a reduction in cardiovascular outcomes (Ezzati, et al. J Epidemiol Community Health. 2012;66[7]:e17).

How do we reconcile such disparate effects of chronic hypoxemia? Part of difference may be in the pattern of chronic intermittent hypoxemia noted with OSA characterized not only by rapid drops in oxygen but also rapid reoxygenation events secondary to arousals terminating an apnea – these reoxygenation events have been attributed to the increased oxidant stress demonstrable in multiple tissues. While chronic hypoxia itself may cause increased oxidant stress, such effects seen with sustained forms of hypoxia, such as sleep-related hypoventilation or high altitude residence, may be more gradual resulting in lesser degrees of tissue effects and regulation of antioxidant defenses with sustained exposure. Herein lies the importance of understanding physiologic and biological effects stemming from chronic hypoxia to explain its variegated effects on different organ systems. In this regard, the role of carotid body, a structure with unique vascular supply and with the ability to respond to minor changes in oxygen saturation as is seen in patients with OSA is key to the causation of hypertension associated with OSA (Shell et al. Curr Hyperten Rep. 2016;18[3]:19). Carotid body activation by intermittent hypoxia and long-term sensory facilitation drives the elevated sympathetic activity and consequent increases in blood pressure that can be improved by supplemental oxygen (Turnbull CD, et al. Am J Respir Crit Care Med. 2019;199[2]:211).

While carotid body responses are key to the pathophysiology of OSA, every organ in the body (in fact, every cell within the body) has the ability to sense and respond to hypoxia. This ability to sense oxygen tensions is ingrained in every cell by virtue of oxygen’s critical role in the genesis of life and evolution. These cellular responses to hypoxia are mediated by hypoxia-inducible factors (HIFs), isoforms of which include the more ubiquitous HIF-1 found in all parenchymal cells and HIF-2 found in specialized erythropoietin-producing cells of the kidney and the pulmonary circulation (the polycythemia and pulmonary vasoconstrictive responses from hypoxia are mediated through HIF-2 ). HIFs mediate the transcription of hundreds of genes, and they have been implicated in the pathobiology of a wide range of phenomena, from cancer to atherosclerotic vascular disease, metabolic syndrome, neurodegenerative disorders, pulmonary hypertension, and nonalcoholic fatty liver disease (Prabhakar and Semenza. Physiol Rev. 2012;92[3]:967). While HIF activation is an attractive target for examining the effects of chronic hypoxia of high altitude and sleep-disordered breathing, HIF activation varies from tissue to tissue and interacts with a number of other cellular systems in leading to differential effects. The short half-life of HIF proteins make them difficult to detect in tissues, so a number of secondary HIF-effects has been measured with mixed results depending on animal model utilized, pattern and degree of hypoxia studied, and the target effect measured. Comparative effects of intermittent vs sustained hypoxemia need to be systematically studied in different organ systems in different species, given the differing oxygen thresholds of individual cells due to unique blood flows and variations in the system of co-factors and prolyl hydroxylases that regulate the activation of HIFs. While the thrust of the work has been centered on HIF-related effects and the role of NF-kB-driven inflammation seen in OSA, there is substantial evidence to the role of oxidant stress that may be directly related to reoxygenation events occurring with CIH (Lavie L. Sleep Med Rev. 2015;20:27).

For life that has been intricately involved with oxygen from its genesis, it is not unreasonable to expect adaptations of cells, organs, and the whole individual to a wide range of oxygen tensions. Attempts to understand the import of sleep-disordered breathing has led to a need to unravel the implications of OSA-related chronic intermittent hypoxia and sleep-hypoventilation. This has led to a resurgence of interest in hypoxia-related research. Whether such chronic sleep-related sustained and intermittent hypoxemia is a harbinger of chronic disease is still not fully clear. A number of challenges exist with the understanding of these chronic hypoxia effects that include the long time needed for disease occurrence, its differential effects on organ systems, the role of hypoxia vs reoxygenation injury, importance of local blood flow, etc. Understanding these pathways will be crucial in prognosticating the role of sleep-related hypoxemia, the recognition of which has become part and parcel of routine management in sleep medicine.

Dr. Sundar is Medical Director, Sleep-Wake Center, Clinical Professor, Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah.