Combined intermittent and sustained hypoxia is a novel and deleterious cardio-metabolic phenotype

Abstract

Study objectives Chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome is associated with excess mortality, and outcomes are related to the degree of hypoxemia. People at high altitude are susceptible to periodic breathing, and hypoxia at altitude is associated with cardio-metabolic dysfunction. Hypoxemia in these scenarios may be described as superimposed sustained plus intermittent hypoxia, or overlap hypoxia (OH), the effects of which have not been investigated. We aimed to characterize the cardio-metabolic consequences of OH in mice. Methods C57BL/6J mice were subjected to either sustained hypoxia (SH, FiO2=0.10), intermittent hypoxia (IH, FiO2=0.21 for 12 hours, and FiO2 oscillating between 0.21 and 0.06, 60 times/hour, for 12 hours), OH (FiO2=0.13 for 12 hours, and FiO2 oscillating between 0.13 and 0.06, 60 times/hour, for 12 hours), or room air (RA), n=8/group. Blood pressure and intraperitoneal glucose tolerance test were measured serially, and right ventricular systolic pressure (RVSP) was assessed. Results Systolic blood pressure transiently increased in IH and OH relative to SH and RA. RVSP did not increase in IH, but increased in SH and OH by 52% (p<0.001) and 20% (p=0.001). Glucose disposal worsened in IH and improved in SH, with no change in OH. Serum LDL and VLDL increased in OH and SH, but not in IH. Hepatic oxidative stress increased in all hypoxic groups, with the highest increase in OH. Conclusions Overlap hypoxia may represent a unique and deleterious cardio-metabolic stimulus, causing systemic and pulmonary hypertension, and without protective metabolic effects characteristic of sustained hypoxia.

The Cardiovascular and Metabolic Effects of Chronic Hypoxia in Animal Models: A Mini-Review

“…Gamboa et al were the first to recognize the potentially beneficial effects of CSH on glucose metabolism ( Gamboa et al, 2011 ), finding that CSH with an FiO 2 of 0.10 reduced plasma fasting glucose and insulin, increased insulin sensitivity, and improved insulin-dependent glucose uptake by skeletal muscle. Since that time, similar findings have been replicated by us ( Zhen et al, 2021 ) and others ( Lee et al, 2013 ; Ioja et al, 2018 ), with additional data demonstrating hypoxia-dependent effects on the liver transcriptome ( Zhen et al, 2021 ) and changes in liver and skeletal muscle mitochondrial function ( Ioja et al, 2018 ). Lipid metabolism also appears to be altered in CSH, with elevated serum triglyceride and low-density lipoprotein levels resulting from CSH with an FiO 2 of 0.10 ( Zhen et al, 2021 ).…”

“…Since that time, similar findings have been replicated by us ( Zhen et al, 2021 ) and others ( Lee et al, 2013 ; Ioja et al, 2018 ), with additional data demonstrating hypoxia-dependent effects on the liver transcriptome ( Zhen et al, 2021 ) and changes in liver and skeletal muscle mitochondrial function ( Ioja et al, 2018 ). Lipid metabolism also appears to be altered in CSH, with elevated serum triglyceride and low-density lipoprotein levels resulting from CSH with an FiO 2 of 0.10 ( Zhen et al, 2021 ). We and others have noted that CSH causes weight loss in rodents.…”

“…We and others have noted that CSH causes weight loss in rodents. In our studies, however, we found a complex interaction between hypoxia and weight, and that beneficial metabolic effects of CSH cannot solely be explained by weight reduction ( Zhen et al, 2021 ).…”

“…However, one study demonstrated that CSH (FiO 2 of 0.10) did change blood pressure in male rats at durations of anywhere from 1 to 30 days, despite an increase in carotid body catecholaminergic signaling ( Hui et al, 2003 ). Our group has also not observed changes in systemic blood pressure in young mice exposed to 40 days of CSH of similar severity ( Zhen et al, 2021 ). Vaziri et al demonstrated increased blood pressure in rats exposed to hypobaric CSH (effective FiO 2 of 0.10–0.11) that persisted even after the restoration of normoxia ( Vaziri and Wang, 1996 ).…”

“…These observations suggested that hypoxemia is likely the most critical of the several physiological manifestations of OSA to cause PH. There are several studies examining the impact of CIH on pulmonary hypertension in rodent models ( Fagan, 2001 ; McGuire and Bradford, 2001 ; Campen et al, 2005 ; Nisbet et al, 2009 ; Nara et al, 2015 ; Snow et al, 2020 ; Zhen et al, 2021 ). Some of these studies appear to show increases in right ventricular systolic pressure, right ventricular mass, and/or pulmonary vascular remodeling in response to CIH, although we did not observe these effects in young C57BL/6J mice ( Zhen et al, 2021 ).…”