Intermittent Hypercapnia Research Articles

The Association of Serum Uric Acid with Risk of Obstructive Sleep Apnea: The Korean National Health and Nutrition Examination Survey 2019-2021.

Upper airway collapse and apneas in obstructive sleep apnea (OSA) induce intermittent hypercapnia and hypoxia, eventually contributing to excessive uric acid production. This study aimed to evaluate the association between hyperuricemia and OSA in the general population via analysis of the eighth KNHANES dataset (2019-2021). OSA risk was identified via the STOP-Bang questionnaire, with a score ≥3 indicating high risk. Among 11,981 total participants, 4572 (38.2%) had a high OSA risk. Participants with a high OSA risk had higher uric acid levels compared to those with a low risk (5.5 ± 1.4 mg/dL vs. 4.8 ± 1.2 mg/dL, p < 0.001). Serum uric acid levels were positively correlated with STOP-Bang score (r: 0.317, p < 0.001). Multivariate analysis revealed that hyperuricemia was associated with a high OSA risk after adjusting for confounders (odds ratio: 1.30, 95%CI: 1.11-1.53, p = 0.001). Therefore, serum uric acid levels are significantly higher in those with a high OSA risk and correlate with the risk of OSA. Further, hyperuricemia is an independently associated risk factor for high OSA risk. More research is warranted to evaluate the long-term clinical outcomes of hyperuricemia in OSA and to determine whether treatment targeting hyperuricemia is effective in the clinical course of OSA.

Breath-Hold-Triggered BOLD fMRI in Drug-Resistant Nonlesional Focal Epilepsy-APilot Study.

Individuals with drug-resistant epilepsy may benefit from epilepsy surgery. In nonlesional cases, where no epileptogenic lesion can be detected on structural magnetic resonance imaging, multimodal neuroimaging studies are required. Breath-hold-triggered BOLD fMRI (bh-fMRI) was developed to measure cerebrovascular reactivity in stroke or angiopathy and highlights regional network dysfunction by visualizing focal impaired flow increase after vasodilatory stimulus. This regional dysfunction may correlate with the epileptogenic zone. In this prospective single-center single-blind pilot study, we aimed to establish the feasibility and safety of bh-fMRI in individuals with drug-resistant non-lesional focal epilepsy undergoing presurgical evaluation. In this prospective study, 10consecutive individuals undergoing presurgical evaluation for drug-resistant focal epilepsy were recruited after case review at amultidisciplinary patient management conference. Electroclinical findings and results of other neuroimaging were used to establish the epileptogenic zone hypothesis. To calculate significant differences in cerebrovascular reactivity in comparison to the normal population, bh-fMRIs of 16healthy volunteers were analyzed. The relative flow change of each volume of interest (VOI) of the atlas was then calculated compared to the flow change of the whole brain resulting in an atlas of normal cerebral reactivity. Consequently, the mean flow change of every VOI of each patient was tested against the healthy volunteers group. Areas with significant impairment of cerebrovascular reactivity had decreased flow change and were compared to the epileptogenic zone localization hypothesis in asingle-blind design. Acquisition of bh-fMRI was feasible in 9/10cases, with one patient excluded due to noncompliance with breathing maneuvers. No adverse events were observed, and breath-hold for intermittent hypercapnia was well tolerated. On blinded review, we observed full or partial concordance of the local network dysfunction seen on bh-fMRI with the electroclinical hypothesis in 6/9cases, including cases with extratemporal lobe epilepsy and those with nonlocalizing 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). This represents the first report of bh-fMRI in individuals with epilepsy undergoing presurgical evaluation. We found bh-fMRI to be feasible and safe, with apromising agreement to electroclinical findings. Thus, bh-fMRI may represent apotential modality in the presurgical evaluation of epilepsy. Further studies are needed to establish clinical utility.

The Effects of Acute Intermittent Hypercapnia on Ventilatory and Cardiovascular Plasticity

Obstructive sleep apnea (OSA) affects over a third of North Americans and is characterized by intermittent bouts of hypoxia combined with hypercapnia during sleep. Intermittent hypoxia and intermittent hypercapnic hypoxia can elicit long-lasting increases in ventilation, blood pressure, and sympathetic nerve activity in humans and may underpin elevated daytime sympathetic activity observed in OSA patients (i.e., long-term facilitation; LTF). Although cardiorespiratory plasticity to intermittent hypoxia and hypercapnic hypoxia are well studied, it is unknown if intermittent hypercapnia (IHc) in the absence of hypoxia leads to cardiorespiratory plasticity in humans. This study aimed to determine if IHc leads to long-lasting effects on ventilation, blood pressure, and vascular conductance. We hypothesized that IHc would lead to long-lasting effects on ventilation, mean arterial pressure (MAP) and limb vascular conductance. Thirteen healthy participants (age: 23±4 years; BMI: 22±2 kg/m2) underwent a 10-minute baseline, 40-minute IHc protocol (40 seconds end-tidal PCO2 +5 mmHg from baseline and 20 seconds of normocapnia), followed by 30-minutes of recovery. Ventilation and MAP were measured continuously, while arm and leg blood flow were collected at the end of baseline and every 10 minutes throughout recovery (strain gauge plethysmography). Limb vascular conductance was calculated as two times the sum of arm and leg blood flow divided by MAP. Data were compared statistically (P&lt;0.05) using mixed effects linear modeling with time (baseline, 10-, 20-, and 30-minutes recovery) as a fixed factor and participant as a random factor. Ventilation (P=0.05), breathing frequency (P=0.2), and tidal volume (P=0.06) were similar to baseline throughout 30-minutes of recovery. There was a main effect of time for MAP (P&lt;0.001), and post hoc analysis indicated that MAP was increased at 10-minutes (Δ7.2mmHg, CI95%: 3.7 – 10.7, P&lt;0.001), 20-minutes (Δ7.7mmHg, CI95%: 4.2 – 11.2, P&lt;0.001), and 30-minutes (Δ8.6mmHg, CI95%: 5.1 – 12.1, P&lt;0.001) following IHc. There was a main effect of time for limb vascular conductance (P=0.001) and post-hoc analysis showed that conductance was reduced at 10-minutes (Δ0.03mmHg, CI95%: -0.05 – -0.01, P=0.007), 20-minutes (Δ0.03mmHg, CI95%: -0.05 – -0.01, P=0.007), and 30-minutes (Δ0.03mmHg, CI95%: -0.05 – -0.01, P=0.006) following IHc. In conclusion, IHc did not lead to ventilatory plasticity but led to long-term facilitation of arterial pressure and reductions in limb conductance. Thus, intermittent hypercapnia may act synergistically with intermittent hypoxia contributing to daytime sympathoexcitation and elevated blood pressure in conditions such as OSA. Funding Sources: American Physiological Society, Natural Sciences and Engineering Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intermittent Exposure of Hypercapnia Suppresses Allograft Rejection via Induction of Treg Differentiation and Inhibition of Neutrophil Accumulation.

Background: In the management of major burn wounds, allogeneic skin transplantation is a critical procedure to improve wound repair. Our previous works found that intermittent exposure to carbon dioxide leads to permissive hypercapnia (HCA) and prolongs skin allograft survival. However, the modulatory effects of HCA exposure on the immune system are not well understood. Objectives: Our purpose was to investigate how intermittent exposure to HCA can effectively reduce the immune reaction to allogeneic skin graft rejection. Methods: A fully major histocompatibility complex-incompatible skin transplant from BALB/c to C57BL/6 mice model was utilized. Immune cells from splenic and draining lymph nodes were analyzed by flow cytometry. Serum proinflammatory cytokines were analyzed by ELISA. Results: Serum levels of IFN-γ, IL-2, IL-6, and TNF-α were significantly decreased in the HCA group. Additionally, the percentage of CD8+ cells in draining lymph nodes was significantly lower in HCA than in the control group. Moreover, the generation rate of FoxP3+ regulatory T cells (Tregs) from spleen naïve CD4+ T cells was increased by intermittent exposure to carbon dioxide. The infiltrated neutrophils were also eliminated by HCA. Taken together, we concluded that intermittent hypercapnia exposure could effectively suppress skin rejection by stimulating Treg cell generation and suppressing immune reactions.

Blockade of alpha2-adrenergic receptors in the caudal raphe region enhances the renal sympathetic nerve activity response to acute intermittent hypercapnia in rats.

The study investigated the role of alpha2-adrenergic receptors of the caudal raphe region in the sympathetic and cardiovascular responses to the acute intermittent hypercapnia (AIHc). Urethane-anesthetized, vagotomized, mechanically ventilated Sprague-Dawley rats (n=38) were exposed to the AIHc protocol (5×3 min, 15 % CO2+50 % O2) in hyperoxic background (50 % O2). alpha2-adrenergic receptor antagonist-yohimbine was applied intravenously (1 mg/kg, n=9) or microinjected into the caudal raphe region (2 mM, n=12) prior to exposure to AIHc. Control groups of animals received saline intravenously (n=7) or into the caudal raphe region (n=10) prior to exposure to AIHc. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were monitored before exposure to the AIHc protocol (T0), during five hypercapnic episodes (THc1-5) and at 15 min following the end of the last hypercapnic episode (T15). Following intravenous administration of yohimbine, RSNA was significantly greater during THc1-5 and at T15 than in the control group (P<0.05). When yohimbine was microinjected into the caudal raphe region, AIHc elicited greater increases in RSNA during THc1-5 when compared to the controls (THc1: 138.0+/-4.0 % vs. 123.7+/-4.8 %, P=0.032; THc2: 137.1+/-5.0 % vs. 124.1+/-4.5 %, P=0.071; THc3: 143.1+/-6.4 % vs. 122.0±4.8 %, P=0.020; THc4: 146.1+/-6.2 % vs. 120.7+/-5.7 %, P=0.007 and THc5: 143.2+/-7.7 % vs. 119.2+/-7.2 %, P=0.038). During THc1-5, significant decreases in HR from T0 were observed in all groups, while changes in MAP were observed in the group that received yohimbine intravenously. These findings suggest that blockade of the alpha2-adrenegic receptors in the caudal raphe region might have an important role in sympathetic responses to AIHc.

Impact of nocturnal oxygen and CPAP on the ventilatory response to hypoxia in OSA patients free of overt cardiovascular disease

A primary characteristic of obstructive sleep apnea (OSA) is chronic exposure to intermittent hypoxia (IH) due to repeated upper airway obstruction. Chronic IH exposure is believed to increase OSA severity over time by enhancing the acute ventilatory response to hypoxia (AHVR), thus promoting ventilatory overshoot when apnea ends and perpetuation of apnea during sleep. Continuous positive airway pressure (CPAP), the gold-standard treatment of OSA, reduces the AHVR, believed to result from correction of IH. However, CPAP also corrects ancillary features of OSA such as intermittent hypercapnia, negative intrathoracic pressure and surges in sympathetic activity, which may also contribute to the reduction in AHVR. Therefore, the objective of this study was to investigate the impact of nocturnal oxygen therapy (to remove IH only) and CPAP (to correct IH and ancillary features of OSA) on AHVR in newly diagnosed OSA patients. Fifty-two OSA patients and twenty-two controls were recruited. The AHVR was assessed using a 5 min iscopanic-hypoxic challenge before, and after, treatment of OSA by nocturnal oxygen therapy and CPAP. Following baseline measurements, OSA patients were randomly assigned to nocturnal oxygen therapy (Oxygen, n = 26) or no treatment (Air; n = 26). The AHVR was re-assessed following two weeks of oxygen therapy or no treatment, after which all patients were treated with CPAP. The AHVR was quantified following ~4 weeks of adherent CPAP therapy (n = 40). Both nocturnal oxygen and CPAP treatments improved hypoxemia (p < 0.05), and, as expected, nocturnal oxygen therapy did not completely abolish respiratory events (i.e., apneas/hypopneas). Averaged across all OSA patients, nocturnal oxygen therapy did not change AHVR from baseline to post-oxygen therapy. Similarly, the AHVR was not altered pre- and post-CPAP (p > 0.05). However, there was a significant decrease in AHVR with both nocturnal oxygen therapy and CPAP in patients in the highest OSA severity quartile (p < 0.05). Nocturnal oxygen therapy and CPAP both reduce the AHVR in patients with the most severe OSA. Therefore, IH appears to be the primary mechanism producing ventilatory instability in patients with severe OSA via enhancement of the AHVR.

Functional Role of Carbon Dioxide on Intermittent Hypoxia Induced Respiratory Response following Mid‐cervical Contusion in the Rat

Intermittent hypoxia can induce ventilatory long-term facilitation, thereby contributing to respiratory motor recovery following spinal cord injury. However, it is unclear whether combination of hypoxia and hypercapnia and strengthen the efficacy of intermittent respiratory stimuli on the respiratory function. Accordingly, the purpose of this study is to evaluate the functional role of intermittent or sustained hypercapnia on intermittent hypoxia-induced respiratory recovery following mid-cervical contusion in the rat. The breathing pattern of unanesthetized rats at the subchronic and chronic injured stages was measured in response to one of the following treatments: (1) Intermittent hypercapnic-hypoxia (10x5 min 10%O2+4%CO2 with 5 min normoxia interval); (2) Intermittent hypoxia with sustained hypercapnia (10x5 min 10%O2+4%CO2 with 5 min 21%O2+4%CO2 interval); (3) Intermittent hypoxia (10x5 min 10%O2 with 5 min normoxia interval); (4) Intermittent hypercapnia (10x5 min 21%O2+4%CO2 with 5 min normoxia interval); (5) Sustained hypercapnia (100 min, 21% O2+4% CO2); (6) Sustained normoxia (100 min, 21% O2). The results demonstrated that the tidal volume was significantly enhanced to a similar magnitude following intermittent hypercapnic-hypoxia, intermittent hypoxia with sustained hypercapnia, and intermittent hypoxia in subchronically injured animals. Nevertheless, only intermittent hypercapnic-hypoxia and intermittent hypoxia were able to evoke long-term facilitation of the tidal volume at the chronic injured stage. Notably, the magnitude of tidal volume recovery is independent on the lesion severity or baseline tidal volume at both subchronic and chronic injured stages. These results suggest that mild intermittent or sustained hypercapnia did not further enhance the therapeutic efficacy of intermittent hypoxia-induced respiratory recovery in mid-cervical contused animals. Future studies are warranted to evaluate whether intermittent hypercapnia or sustained hypercapnia can modulate the respiratory function following daily intermittent hypoxia training.

Influence of Intermittent Hypoxia/Hypercapnia on Atherosclerosis, Gut Microbiome, and Metabolome.

Obstructive sleep apnea (OSA), a common sleep disorder characterized by intermittent hypoxia and hypercapnia (IHC), increases atherosclerosis risk. However, the contribution of intermittent hypoxia (IH) or intermittent hypercapnia (IC) in promoting atherosclerosis remains unclear. Since gut microbiota and metabolites have been implicated in atherosclerosis, we examined whether IH or IC alters the microbiome and metabolome to induce a pro-atherosclerotic state. Apolipoprotein E deficient mice (ApoE−/−), treated with IH or IC on a high-fat diet (HFD) for 10 weeks, were compared to Air controls. Atherosclerotic lesions were examined, gut microbiome was profiled using 16S rRNA gene amplicon sequencing and metabolome was assessed by untargeted mass spectrometry. In the aorta, IC-induced atherosclerosis was significantly greater than IH and Air controls (aorta, IC 11.1 ± 0.7% vs. IH 7.6 ± 0.4%, p < 0.05 vs. Air 8.1 ± 0.8%, p < 0.05). In the pulmonary artery (PA), however, IH, IC, and Air were significantly different from each other in atherosclerotic formation with the largest lesion observed under IH (PA, IH 40.9 ± 2.0% vs. IC 20.1 ± 2.6% vs. Air 12.2 ± 1.5%, p < 0.05). The most differentially abundant microbial families (p < 0.001) were Peptostreptococcaceae, Ruminococcaceae, and Erysipelotrichaceae. The most differentially abundant metabolites (p < 0.001) were tauro-β-muricholic acid, ursodeoxycholic acid, and lysophosphoethanolamine (18:0). We conclude that IH and IC (a) modulate atherosclerosis progression differently in distinct vascular beds with IC, unlike IH, facilitating atherosclerosis in both aorta and PA and (b) promote an atherosclerotic luminal gut environment that is more evident in IH than IC. We speculate that the resulting changes in the gut metabolome and microbiome interact differently with distinct vascular beds.

The microbiome in obstructive sleep apnea.

Recent evidence has highlighted important associations between obstructive sleep apnea and the microbiome. Although the intricacies of the pathophysiologic mechanisms are not well understood, available evidence suggests a bidirectional relationship between obstructive sleep apnea and microbiota composition. Sleep fragmentation, intermittent hypoxia, and intermittent hypercapnia all play significant roles in altering the microbiome, and initial evidence has shown that alterations of the microbiota affect sleep patterns. Animal model evidence strongly supports the idea that the microbiome mediates disease states associated with obstructive sleep apnea including hypertension, atherosclerosis, and obesity. While evidence is limited, several studies suggest there may be a role for treatment of obstructive sleep apnea and obstructive sleep apnea-related comorbidities through alteration of the microbiome with probiotics, prebiotics, and microbiota transplantation.

Functional role of carbon dioxide on intermittent hypoxia induced respiratory response following mid-cervical contusion in the rat

Intermittent hypoxia induces respiratory neuroplasticity to enhance respiratory motor outputs and is a potential rehabilitative strategy to improve respiratory function following cervical spinal injury. The present study was designed to evaluate the functional role of intermittent and sustained carbon dioxide (CO2) on intermittent hypoxia-induced ventilatory responses in rats with mid-cervical spinal contusion. The breathing pattern of unanesthetized rats at the subchronic and chronic injured stages was measured in response to one of the following treatments: (1) Intermittent hypercapnic-hypoxia (10 × 5 min 10%O2 + 4%CO2 with 5 min normoxia interval); (2) Intermittent hypoxia with sustained hypercapnia (10 × 5 min 10%O2 + 4%CO2 with 5 min 21%O2 + 4%CO2 interval); (3) Intermittent hypoxia (10 × 5 min 10%O2 with 5 min normoxia interval); (4) Intermittent hypercapnia (10 × 5 min 21%O2 + 4%CO2 with 5 min normoxia interval); (5) Sustained hypercapnia (100 min, 21% O2 + 4% CO2); (6) Sustained normoxia (100 min, 21% O2). The results demonstrated that intermittent hypoxia associated with intermittent hypercapnia or sustained hypercapnia induced a greater ventilatory response than sustained hypercapnia during stimulus exposure. The tidal volume was significantly enhanced to a similar magnitude following intermittent hypercapnic-hypoxia, intermittent hypoxia with sustained hypercapnia, and intermittent hypoxia in subchronically injured animals; however, only intermittent hypercapnic-hypoxia and intermittent hypoxia were able to evoke long-term facilitation of the tidal volume at the chronic injured stage. These results suggest that mild intermittent hypercapnia did not further enhance the therapeutic effectiveness of intermittent hypoxia-induced respiratory recovery in mid-cervical contused animals. However, sustained hypercapnia associated with intermittent hypoxia may blunt ventilatory responses following intermittent hypoxia at the chronic injured stage.

Hyperoxia blunts renal sympathetic nerve activity response to acute intermittent hypercapnia in rats.

Activation of the sympathetic nervous system plays an important role in the pathophysiology of sleep-related breathing disorders. The aim of the present study was to examine the effects of different levels of hypercapnia in the presence of various background oxygen levels on the magnitude of sympathoexcitation, measured by the renal sympathetic nerve activity (RSNA) in the acute intermittent hypercapnia (AIHc) rat model. The study was conducted on 56 urethane-anesthetized, vagotomized and mechanically ventilated Sprague-Dawley rats (n = 7/group). Each experimental group was subjected to a distinct AIHc protocol that varied in the applied levels of hypercapnia and background oxygen. Mean arterial pressure and RSNA were analyzed in 7 experimental time points: baseline, five hypercapnic episodes (each lasting 3 min) and 15 minutes following the last hypercapnic episode. Exposure to severe hypercapnia (FiCO2 = 0.15) evoked an increase in RSNA, which was preserved throughout the protocol, whereas in moderate hypercapnia (FiCO2 = 0.05) groups there was a trend of progressive diminution of RSNA magnitude following the first hypercapnic episode. Exposure to severe hypercapnia elicited significantly greater RSNA response during first hypercapnic episode and it was enhanced during subsequent episodes compared to exposure to moderate hypercapnia. Additionally, hyperoxic2 background (50% O2) blunted the RSNA response to AIHc compared to room air background, both in severe and moderate hypercapnia groups. Mean arterial blood pressure was preserved throughout the experimental protocol in all studied groups. These findings indicate that acute intermittent hypercapnia evokes increased renal sympathetic nerve activity that is dependent on the severity of hypercapnic exposures and the background oxygen level.

СОСТОЯНИЕ КИСЛОРОДТРАНСПОРТНОЙ ФУНКЦИИ КРОВИ ПРИ СИНДРОМЕ ОБСТРУКТИВНОГО АПНОЭ/ГИПОПНОЭ СНА

Summary. Оbstructive sleep apnea / hypopnea syndrome (OSAHS) is a topical medical problem and can lead to important medical consequences. OSAHS-associated biological changes are caused by periodic hypoxia and intermittent hypercapnia. The state and clinical significance of the oxygen transport function in OSAHS have not been studied and this was the purpose of the present research. The obtained results indicated the development of compensated metabolic acidosis during OSAHS: an increase in the lactate level with pH being within normal limits. There was a decrease in hemoglobin-oxygen affinity (a shift of oxyhemoglobin dissociation curve rightwards), regulating processes of tissues oxygenation during hypoxia. There also was a positive compensatory reaction in OSAHS. The identified changes correlated with the severity of sleep apnea.

Different Impacts of Intermittent Hypoxia and Hypercapnia on Atherosclerotic Formation

Obstructive sleep apnea (OSA) is a common disorder characterized by intermittent hypoxia and hypercapnia (IHC) during sleep and has been considered a risk for atherosclerosis. However, the particular role of intermittent hypoxia (IH), intermittent hypercapnia (IC) or their combination (IHC) in inducing or promoting atherosclerosis remains obscure. To dissect the mechanisms involved, we examined atherosclerotic formation in the Aorta, Aortic arch and Pulmonary artery (PA) in pro‐atherogenesis mouse model apolipoprotein E (ApoE) deficient mice, after IHC, IH, or IC exposure on high fat diet (HFD) as compared to room air (RA) groups either under HFD or regular chow (RC). Our data revealed that all HFD‐treated mice exhibited more atherosclerotic lesions than those fed with RC (e.g. Aorta, RA‐HFD 8.1±0.8% vs RA‐RC 1.0±0.3%, p&lt;0.01). 10‐week IHC treatment expedited atherosclerosis in Aorta, Aortic arch and PA as compared to room air controls in the presence of HFD (Aorta, IHC‐HFD 13.8±1.0% vs RA‐HFD 8.1±0.8%, p&lt;0.01; Aortic arch, IHC‐HFD 28.5±1.9% vs RA‐HFD 16.6±2.0%, p&lt;0.01; PA, IHC‐HFD 28.9±2.8% vs RA‐HFD 12.2±1.5%, p&lt;0.01). Furthermore, IHC‐induced atherosclerosis in Aorta was significantly greater than in IC or IH (Aorta, IHC‐HFD 13.8±1.0% vs either IH‐HFD 7.6±0.4%, p&lt;0.01 or IC‐HFD 11.1±0.7%, p&lt;0.05), indicating that the effect of IHC is the result of potential interactions between IC and IH. Interestingly, in the PA, the largest atherosclerotic formation was observed in IH‐treated mice, followed by IHC then IC (PA, IH‐HFD 40.9±2.0% vs either IHC‐HFD 28.9±2.8%, p&lt;0.01 or IC‐HFD 20.1±2.6%, p&lt;0.01), suggesting that (a) IH has a greater effect on the PA than on the Aorta and (b) IC may alleviate IH‐ or IHC‐induced lesion in the PA. Our findings suggest that (1) IH, IC and IHC affect the development of atherosclerosis differently and (2) distinct vasculatures (Aorta and Pulmonary artery) react to IHC, IH, IC differently in atherogenesis.Support or Funding InformationSupported by the National Institutes of Health grant 5 P01 32573 (G.G.H.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Metabolic and cardiovascular responses to chronic intermittent hypoxia and hypercapnia

Obstructive sleep apnea exposes individuals to chronic intermittent hypoxia‐hypercapnia (CIHH) episodes and it is associated with increases in sympathetic nervous system activity and blood pressure (BP). Previous experimental studies utilized mainly exposure to chronic intermittent hypoxia (CIH) alone without hypercapnia. In this study we examined if CIHH potentiates the pressor and metabolic responses compared to CIH alone. Sprague‐Dawley rats were instrumented with telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR) 24‐hrs/day. Rats (n=10) were exposed to CIH (7% O2, 8 hrs/day from 8:00–16:00 hours for 5 consecutive days) or CIHH (7% O2 plus 8% CO2, 8 hrs/day from 8:00–16:00 hours for 5 consecutive days). CIHH and CIH reduced food intake similarly (21±1 to 17±1 vs. 16±1 to 14±1 g/day) leading to a net cumulative decrease in food intake of −22 and −21g, respectively. No changes were observed in plasma glucose concentrations. However, MAP response to CIHH was attenuated by 30% compared to CIH alone (+7±1 vs. +10±1 mmHg). CIHH also induced bradycardia when compared to CIH alone (−24±4 vs. +3±4 bpm, respectively). These results show that combining hypoxia with hypercapnia attenuates the rise in MAP and reduces HR without altering blood glucose and food intake when compared to hypoxia alone. Thus, chronic intermittent hypoxia, but not intermittent hypercapnia, appears to contribute to elevated MAP in rats (NHLBI‐PO1HL51971, NIGMS P20GM104357, NIGMS U54GM115428)Support or Funding InformationNHLBI‐PO1HL51971, NIGMS P20GM104357, NIGMS U54GM115428This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vascular responses to hypoxia are not impaired in obstructive sleep apnoea patients free of overt cardiovascular disease.

What is the central question of this study? Does treatment of obstructive sleep apnoea (OSA) with nocturnal oxygen or continuous positive airway pressure (CPAP) improve hypoxic vascular responses, which are reportedly impaired in OSA? What is the main finding and its importance? Cerebrovascular and cardiovascular hypoxic responses were not impaired in OSA patients free of overt cardiovascular disease and known risk factors, and were not altered by nocturnal oxygen or CPAP treatment. We conclude that this OSA patient phenotype has normal vascular responses to hypoxia and is unlikely to obtain long term cardiovascular benefits from nocturnal oxygen or CPAP therapy. Cerebral blood flow (CBF) and cardiovascular responses to hypoxia are reportedly impaired in obstructive sleep apnoea (OSA) patients and corrected by continuous positive airway pressure (CPAP), beneficial effects that are ascribed to correction of OSA-related intermittent hypoxia (IH). However, CPAP corrects both IH and ancillary OSA features (i.e. intermittent hypercapnia, sympathetic activation, blood pressure surges, negative intrathoracic pressure swings and sleep fragmentation). Whether correction of these ancillary OSA features contribute to CPAP's beneficial effects on vascular hypoxic responses is unknown. Nocturnal oxygen corrects OSA-induced IH, but apnoeas and ancillary features persist. Thus, we examined the effects of nocturnal oxygen and CPAP on cerebrovascular and cardiovascular hypoxic responses in untreated OSA patients. Responses were assessed in 52 OSA patients free of overt cardiovascular disease and known risk factors at baseline, after 2weeks of nocturnal oxygen (n=26) or no treatment (n=26), and after ∼4weeks of CPAP treatment (n=40). Twenty-two age-matched controls were assessed at baseline and follow-up visits. Resting, isocapnic euoxia mean blood pressure was decreased following nocturnal oxygen (-3.6±6.0mmHg; P=0.006) and CPAP (-4.5±7.5mmHg; P<0.001) while cerebrovascular conductance was increased with CPAP (P=0.001). However, these changes were not different from controls. Unexpectedly, OSA patients and controls had similar hypoxic vascular responses at baseline that were not changed by either nocturnal oxygen or CPAP. We conclude that OSA patients free of overt cardiovascular disease and known risk factors did not have impaired cerebrovascular or cardiovascular responses to hypoxia and are unlikely to obtain long term cardiovascular benefits from nocturnal oxygen or CPAP therapy.

Phrenic long-term depression evoked by intermittent hypercapnia is modulated by serotonergic and adrenergic receptors in raphe nuclei.

Intermittent hypercapnia evokes prolonged depression of phrenic nerve activity (phrenic long-term depression, pLTD). This study was undertaken to investigate the role of 5-HT and α2-adrenergic receptors in the initiation of pLTD. Adult male urethane-anesthetized, vagotomized, paralyzed, and mechanically ventilated Sprague-Dawley rats were exposed to a protocol of acute intermittent hypercapnia (AIHc; 5 episodes of 15% CO2 in air, each episode lasting 3 min). The experimental group received microinjection of the selective 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), the broad-spectrum 5-HT antagonist methysergide, or the α2-adrenergic antagonist yohimbine, whereas the control group received microinjection of 0.9% saline into the caudal raphe region. Peak phrenic nerve activity (pPNA) and burst frequency ( f) were analyzed during baseline (T0), during 5 hypercapnic episodes (THc1-THc5), and at 15, 30, and 60 min after the end of the last hypercapnic episode. In the control group, pPNA decreased 60 min after the end of the last hypercapnic episode compared with baseline values, i.e., pLTD developed ( P = 0.023). In the 8-OH-DPAT group, pPNA significantly decreased at T15, T30, and T60 compared with baseline values, i.e., pLTD developed ( P = 0.01). In the methysergide and yohimbine groups, AIHc did not evoke significant changes of the pPNA at T15, T30, and T60 compared with baseline values. In conclusion, activation of 5-HT1A receptors accentuated induction of pLTD, whereas blockade of α2-adrenergic receptors prevented development of pLTD following AIHc in anesthetized rats. These results suggest that chemical modulation of 5-HT and α2-adrenergic receptors in raphe nuclei affects hypercapnia-induced pLTD, offering important insights in understanding the mechanisms involved in development of respiratory plasticity. NEW & NOTEWORTHY Hypercapnia is a concomitant feature of many breathing disorders, including obstructive sleep apnea. In this study, acute intermittent hypercapnia evoked development of phrenic long-term depression (pLTD) 60 min after the last hypercapnic episode that was preserved if the selective 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide was microinjected in the caudal raphe region before the hypercapnic stimulus. This study highlights that both 5-HT and adrenergic receptor activation is needed for induction of pLTD in urethane-anesthetized rats following intermittent hypercapnia exposure.

The Influence of CO2 and Exercise on Hypobaric Hypoxia Induced Pulmonary Edema in Rats.

Introduction: Individuals with a known susceptibility to high altitude pulmonary edema (HAPE) demonstrate a reduced ventilation response and increased pulmonary vasoconstriction when exposed to hypoxia. It is unknown whether reduced sensitivity to hypercapnia is correlated with increased incidence and/or severity of HAPE, and while acute exercise at altitude is known to exacerbate symptoms the effect of exercise training on HAPE susceptibility is unclear.Purpose: To determine if chronic intermittent hypercapnia and exercise increases the incidence of HAPE in rats.Methods: Male Wistar rats were randomized to sedentary (sed-air), CO2 (sed-CO2,) exercise (ex-air), or exercise + CO2 (ex-CO2) groups. CO2 (3.5%) and treadmill exercise (15 m/min, 10% grade) were conducted on a metabolic treadmill, 1 h/day for 4 weeks. Vascular reactivity to CO2 was assessed after the training period by rheoencephalography (REG). Following the training period, animals were exposed to hypobaric hypoxia (HH) equivalent to 25,000 ft for 24 h. Pulmonary injury was assessed by wet/dry weight ratio, lung vascular permeability, bronchoalveolar lavage (BAL), and histology.Results: HH increased lung wet/dry ratio (HH 5.51 ± 0.29 vs. sham 4.80 ± 0.11, P < 0.05), lung permeability (556 ± 84 u/L vs. 192 ± 29 u/L, P < 0.001), and BAL protein (221 ± 33 μg/ml vs. 114 ± 13 μg/ml, P < 0.001), white blood cell (1.16 ± 0.26 vs. 0.66 ± 0.06, P < 0.05), and platelet (16.4 ± 2.3, vs. 6.0 ± 0.5, P < 0.001) counts in comparison to normobaric normoxia. Vascular reactivity was suppressed by exercise (−53% vs. sham, P < 0.05) and exercise+CO2 (−71% vs. sham, P < 0.05). However, neither exercise nor intermittent hypercapnia altered HH-induced changes in lung wet/dry weight, BAL protein and cellular infiltration, or pulmonary histology.Conclusion: Exercise training attenuates vascular reactivity to CO2 in rats but neither exercise training nor chronic intermittent hypercapnia affect HH- induced pulmonary edema.

Hypercapnia Accelerates Adipogenesis: A Novel Role of High CO2 in Exacerbating Obesity.

Obesity is a major risk factor for the development of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS), which manifest as intermittent hypercapnia and sustained plus intermittent hypercapnia, respectively. In this study, we investigated whether CO2 affects adipocyte differentiation (adipogenesis) and maturation (hypertrophy). Human visceral or subcutaneous preadipocytes were grown to confluence and then induced to differentiate to adipocytes under hypocapnia, normocapnia, and hypercapnia with or without hypoxia. Adipogenesis was also induced under intermittent or sustained hypercapnia. Differentiated adipocytes were maintained to maturity under normocapnia or hypercapnia. Our main findings are as follows: (1) hypercapnia accelerated adipogenesis in visceral and subcutaneous preadipocytes, whereas hypocapnia inhibited adipogenesis; (2) hypercapnia did not affect adipocyte hypertrophy; (3) hypercapnia-accelerated adipogenesis was independent of extracellular acidosis, oxygen concentration, or either intermittent or sustained exposure to high CO2; and (4) the mechanisms underlying hypercapnia-accelerated adipogenesis involved increased production of cyclic adenosine monophosphate (cAMP) via soluble adenylyl cyclase, leading to the activation of protein kinase A and exchanger protein directly activated by cAMP, which, in turn, activated proadipogenic transcription factors, such as cAMP response element binding protein, CCAAT/enhancer binding protein β, and peroxisome proliferator-activated receptor γ. This study reveals a novel role of high CO2 in promoting adipogenesis, which provides mechanistic clues to a pathoetiological interaction between OSA/OHS and obesity. Our data suggest a vicious cycle of disease progression via the following mechanism: OSA/OHS → hypoventilation → hypercapnia → increased adipogenesis → increased fat mass → exacerbated OSA/OHS.

P 83 Parasomnia, parkinsonism, impulse control disorder and bulbar palsy with IgLON5 antibodies: A new case report

Background In 2014 a complex neurological syndrome with parasomnia, sleep breathing dysfunction and variable bulbar symptoms associated with antibodies to IgLON5, a neuronal cell-adhesion protein, was described (Sabater et al., 2016). Postmortal studies revealed tauopathy predominately involving the hypothalamus and tegmentum of the brainstem (Gelpi et al., 2016). To the best of our knowledge, there are 16 published cases so far. Methods (clinical presentation) We report a 72-year-old highly educated male Caucasian patient with a 6 year history of parasomnia with RBD in the beginning, following of multiple falls, parkinsonism, hypomania, frontal lobe disorder and impulse control disorder (ICD; leading to sentence of detention) with aggressive tendencies. By transcranial ultrasound hyperechogenicity of substantia nigra was demonstrated, FDG-PET imaging showed lower 18F-FDG activity in temporal lobes. Thus idiopathic Parkinson’s disease was assumed. Due to neuropsychiatric complications the antiparkinson medication was gradually reduced and eventually discontinued in 2014. Interestingly, there were no relevant changes in symptoms of parkinsonism thereafter. In 2016, after acute coronary syndrome the patient developed a sudden bilateral vocal cord paresis with stridor leading to intubation and following tracheotomy. Subsequently, he showed dysphagia, increasing rigidity, fluctuating level of consciousness with intermittent hypoventilation and hypercapnia, and autonomic dysregulation. Critical decompensation with need of short CPR occurred twice, continuous monitoring with mechanical ventilation was required. Results (workup and treatment, Table 1 ) Brain MRI showed iron accumulation in globus pallidus and dentate nucleus, and a small pineal cyst ( Fig. 1 a). The initial multiple EEGs were normal. Diverse EEGs from 2016 registered generalized slowing with intermittent hyperexcitability; nonconvulsive status epilepticus was captured once ( Fig. 1 b). Laboratory tests displayed neutrophil leukocytosis with MGUS IgG-kappa and -lambda. In serum (1:100) and in CSF (1:10) IgLON5 antibodies (IgG subclass) were detected. HLA-typing revealed HLA-DRB1∗10:01 and HLA-DQB1∗05:01 alleles. Tumor screening (thoracic and abdominal CT, bone marrow examination) did not detect malignancy. Because of suspected IgLON5-syndrome with autoimmune origin an immunosuppressive therapy with initial IV methylprednisolone pulse therapy following oral prednisolone (75 mg/d) and rituximab was initiated. Subsequently, after achieving better vigilance, it was possible to start weaning again. Conclusion Parasomnia, ICD, beginning frontal lobe syndrome with parkinsonism, multiple falls and bulbar symptoms is a new combination in IgLON5 antibody-linked syndrome. A connection to neurodegeneration with brain iron accumulation (NBIA) is possible and requires further investigation.

Independent associations between arterial bicarbonate, apnea severity and hypertension in obstructive sleep apnea

BackgroundObstructive sleep apnea is characterized by intermittent hypoxia and hypercapnia. CO2 production, transport and elimination are influenced by the carbonic anhydrase enzyme. We hypothesized that elevated standard bicarbonate, a proxy for increased carbonic anhydrase activity, is associated with apnea severity and higher blood pressure in patients with obstructive sleep apnea.MethodsA retrospective analysis of a sleep apnea cohort (n = 830) studied by ambulatory polygraphy. Office systolic/diastolic blood pressure, lung function, and arterial blood gases were assessed during daytime.ResultsArterial standard bicarbonate was increased with apnea severity (mild/moderate/severe 24.1 ± 1.8, 24.4 ± 1.7 and 24.9 ± 2.9 mmol/l, respectively, Kruskal-Wallis test p < 0.001). Standard bicarbonate was independently associated with apnea hypopnea index after adjustment for sex, age, body mass index, smoking, alcohol, hypertension, pO2 and pCO2 (standard bicarbonate quartile 1 vs. quartile 4, β = 10.6, p < 0.001). Log-transformed standard bicarbonate was associated with a diagnosis of hypertension or diastolic blood pressure but not systolic blood pressure adjusting for cofounders (p = 0.007, 0.048 and 0.45, respectively).ConclusionsThere was an independent association between sleep apnea severity and arterial standard bicarbonate. The link between high standard bicarbonate and daytime hypertension suggests that carbonic anhydrase activity may constitute a novel mechanism for blood pressure regulation in sleep apnea.