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Biomedical subjects

Alan R Schwartz

Publications and source records attributed to Alan R Schwartz.

At least 19 recordsLinked to original sources
PubMed2006

Neuromechanical control of upper airway patency during sleep.

Obstructive sleep apnea is caused by pharyngeal occlusion due to alterations in upper airway mechanical properties and/or disturbances in neuromuscular control. The objective of the study was to determine the relative contribution of mechanical loads and dynamic neuromuscular responses to pharyngeal collapse during sleep. Sixteen obstructive sleep apnea patients and sixteen normal subjects were matched on age, sex, and body mass index. Pharyngeal collapsibility, defined by the critical pressure, was measured during sleep. The critical pressure was partitioned between its passive mechanical properties (passive critical pressure) and active dynamic responses to upper airway obstruction (active critical pressure). Compared with normal subjects, sleep apnea patients demonstrated elevated mechanical loads as demonstrated by higher passive critical pressures [-0.05 (SD 2.4) vs. -4.5 cmH2O (SD 3.0), P = 0.0003]. Dynamic responses were depressed in sleep apnea patients, as suggested by failure to lower their active critical pressures [-1.6 (SD 3.5) vs. -11.1 cmH2O (SD 5.3), P < 0.0001] in response to upper airway obstruction. Moreover, elevated mechanical loads placed some normal individuals at risk for sleep apnea. In this subset, dynamic responses to upper airway obstruction compensated for mechanical loads and maintained airway patency by lowering the active critical pressure. The present study suggests that increased mechanical loads and blunted neuromuscular responses are both required for the development of obstructive sleep apnea.

Adult↗
PubMed2006

Dynamic modulation of upper airway function during sleep: a novel single-breath method.

To examine the dynamic modulation of upper airway (UA) function during sleep, we devised a novel approach to measuring the critical pressure (Pcrit) within a single breath in tracheostomized sleep apnea patients. We hypothesized that the UA continuously modulates airflow dynamics during transtracheal insufflation. In this study, we examine tidal pressure-flow relationships throughout the respiratory cycle to compare phasic differences in UA collapsibility between closure and reopening. Five apneic subjects (with tracheostomy) were recruited (2 men, 3 women; 18-50 yr; 20-35 kg/m2; apnea-hypopnea index >20) for this polysomnographic study. Outgoing airflow through the UA (face mask pneumotachograph) and tracheal pressure were recorded during brief transtracheal administration of insufflated airflow via a catheter. Pressure-flow relationships were generated from deflation (approaching Pcrit) and inflation (after Pcrit) of the UA during non-rapid eye movement sleep. During each breath, UA function was described by a pressure-flow relationship that defined the collapsibility (Pcrit) and upstream resistance (Rus). UA characteristics were examined in the presence and absence of complete UA occlusion. We demonstrated that Pcrit and Rus changed dynamically throughout the respiratory cycle. The UA closing pressure (4.4 +/- 2.0 cm H2O) was significantly lower than the opening pressure (10.8 +/- 2.4 cm H2O). Rus was higher for deflation (18.1 +/- 2.4 cm H2O x l(-1) x s) than during inflation (7.5 +/- 1.9 cm H2O x l(-1) x s) of the UA. Preventing occlusion decreases UA pressure-flow loop hysteresis by approximately 4 cm H2O. These findings indicate that UA collapsibility varies dynamically throughout the respiratory cycle and that both local mechanical and neuromuscular factors may be responsible for this dynamic modulation of UA function during sleep.

Adolescent↗
PubMed2006

Upper airway collapsibility in anesthetized children.

We sought to establish the feasibility of measuring upper airway narrowing in spontaneously breathing, anesthetized children using dynamic application of negative airway pressure. A secondary aim was to compare differences in upper airway collapsibility after the administration of sevoflurane or halothane. Subjects were randomized to either drug for inhaled anesthetic induction. Each was adjusted to their 1 MAC value (0.9% for halothane and 2.5% for sevoflurane) and a blinded anesthesia provider held the facemask without performing manual airway opening maneuvers but with inclusion of an oral airway device. Inspiratory flows were measured during partial upper airway obstruction created by an adjustable negative pressure-generating vacuum motor inserted into the anesthesia circuit. Critical closing pressure of the pharynx (Pcrit) was obtained by plotting the peak inspiratory flow of the obstructed breaths against the corresponding negative pressure in the facemask and extrapolating to zero airflow using linear correlation. Fourteen children were enrolled, seven in each anesthetic group. Two children in the halothane group did not develop flow-limited airway obstruction despite negative pressures as low as -9 cm H2O. Pcrit for sevoflurane ranged from -6.7 to -11.6 (mean +/- sd, -9.8 +/- 1.9) cm H2O. Pcrit for halothane ranged from -8.1 to -33 (mean +/- sd, -19.4 +/- 9.3) cm H2O (sevoflurane versus halothane, P = 0.048). We conclude that when using dynamic application of negative airway pressure, halothane appears to cause less upper airway obstruction than sevoflurane at equipotent concentrations.

Airway Obstruction↗
PubMed2005

Intermittent hypoxia causes REM sleep deficits and decreases EEG delta power in NREM sleep in the C57BL/6J mouse.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) severely impairs sleep architecture. We hypothesized that both intermittent hypoxia (IH) and non-hypoxic arousals of OSA result in significant disruption of non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). PATIENTS AND METHODS: Polysomnography was performed in C57BL/6J mice (n=5) exposed to IH (cycling of FIO2 from 20.9 to 5.0%) or sleep fragmentation (SF: high flow air blasts) throughout the 12-h light phase over 5 consecutive days. RESULTS: Both IH and SF induced arousals from sleep. On Day 1 of exposure, total NREMS during the light phase decreased comparably during IH (44.1+/-7.8%/12h, P<0.05) and SF (43.7+/-3.3%/12h, P<0.05) but returned to baseline levels of 62.0+/-7.8%/12h by Day 5 of exposure under both conditions. During IH, however, the electroencephalographic (EEG) delta power of NREMS remained impaired throughout the 5-day period of IH with a nadir of 65.4+/-5.6% relative to baseline (P=0.01), and REMS was effectively abolished during the light phase. In contrast, SF did not cause a significant reduction in either EEG delta power or REMS during the light phase. CONCLUSIONS: Thus, hypoxic exposure, but not arousals, caused overall deficits in the EEG delta power of NREMS and marked deficits in the total amount of REMS. We propose that hypoxic arousals may have a more severe impact on sleep architecture in patients with OSA than non-hypoxic arousals.

Animals↗
PubMed2005

Intermittent hypoxia induces hyperlipidemia in lean mice.

Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep(ob) mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity.

Animals↗
PubMed2005

Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice.

Obstructive sleep apnea (OSA), a condition tightly linked to obesity, leads to chronic intermittent hypoxia (CIH) during sleep. There is emerging evidence that OSA is independently associated with insulin resistance and fatty liver disease, suggesting that OSA may affect hepatic lipid metabolism. To test this hypothesis, leptin-deficient obese (ob/ob) mice were exposed to CIH during the light phase (9 AM-9 PM) for 12 wk. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with real-time PCR validation) were determined on completion of the exposure. CIH caused a 30% increase in triglyceride and phospholipid liver content (P < 0.05), whereas liver cholesterol content was unchanged. Gene expression analysis showed that CIH upregulated multiple genes controlling 1) cholesterol and fatty acid biosynthesis [malic enzyme and acetyl coenzyme A (CoA) synthetase], 2) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase and stearoyl-CoA desaturases 1 and 2), and 3) triglyceride and phospholipid biosynthesis (mitochondrial glycerol-3-phosphate acyltransferase). A majority of overexpressed genes were transcriptionally regulated by sterol regulatory element-binding protein (SREBP) 1, a master regulator of lipogenesis. A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (P = 0.001). Expression of major genes of cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate preexisting fatty liver of obesity via upregulation of the pathways of lipid biosynthesis in the liver.

Animals↗
PubMed2004

A simplified method for measuring critical pressures during sleep in the clinical setting.

Upper airway critical pressure measurements correlate with the degree of upper airway obstruction during sleep and may have a role in the diagnosis and treatment of obstructive sleep apnea. Nevertheless, the utility of the critical pressure has not yet been realized in the clinical setting because significant technical expertise is still required for the acquisition and analysis of pressure-flow data. Using segmented regression, we developed and validated a simplified approach to analyze the pressure-flow relationship and to determine the effects of protocol-related factors in 44 subjects with sleep apnea. When compared with expert visual analysis, segmented regression method was found to accurately determine the critical pressure (-0.98 +/- 2.47 cm H(2)O vs. -1.07 +/- 2.47 cm H(2)O, respectively; p = 0.46). Furthermore, it was found that two series of measurements acquired at varying nasal pressure levels with two or more breaths per level were sufficient to determine the critical pressure with a minimum of variability. Therefore, this analytic approach has the potential for standardizing and simplifying the ascertainment of the critical pressure for studies examining the effect of therapeutic devices and agents on upper airway collapsibility during sleep.

Airway Resistance↗
PubMed2003

Impact of interrupted leptin pathways on ventilatory control.

Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response, particularly during sleep. We now extend our previous findings to determine whether 1) leptin deficiency affects the hypoxic ventilatory response and 2) blockade of the downstream excitatory actions of leptin on melanocortin 4 receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same hypoxic ventilatory response as weight-matched wild-type obese mice. There were no differences in the hypoxic sensitivity between agouti yellow mice and weight-matched controls, or NPY-deficient mice and wild-type littermates. Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 +/- 0.7 vs. 8.9 +/- 0.7 ml x min(-1) x %CO(2)(-1), P < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the hypercapnic ventilatory response compared with wild-type littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep.

Animals↗
PubMed2003

Differences in sleep-induced hypoxia between A/J and DBA/2J mouse strains.

In obstructive sleep apnea, hypoxic ventilatory sensitivity may affect the degree of hypoxic stress and sleep disruption that occurs in response to upper airway obstruction. We induced (1) sleep-induced hypoxia (SIH) or (2) sleep fragmentation (SF) without hypoxia for 5 days (12-hour light/dark cycle) in two inbred mouse strains with low (A/J) and high (DBA/2J) hypoxic ventilatory sensitivities. During SIH, the time to arousal (26.4 +/- 1.1 vs. 21.3 +/- 1.5 seconds, p<0.025) and the severity of hypoxic exposure (nadir FIO2: 11.5 +/- 0.4 vs. 13.6 +/- 0.1%, p<0.002) was greater in A/J than DBA/2J mice. Furthermore, A/J mice had a greater frequency of hypoxic events (640 +/- 29 vs. 368 +/- 33 events per 24 hours, p<0.001) and total sleep time (47.5 +/- 2.8% vs. 26.5 +/- 2.4% per 24 hours, p<0.0001) during SIH than DBA/2J mice. In contrast, the event characteristics and total sleep time during SF were the same in both strains. Furthermore, in the light phase, both strains showed a longer (p<0.01) time to arousal during SIH and SF compared with the dark phase. We conclude that genetic background can influence respiratory events and sleep architecture during SIH and that the arousal threshold is subject to circadian variation. Our data imply that individuals with low hypoxic sensitivity may be at a greater risk for hypoxia-related complications of obstructive sleep apnea.

Animals↗
PubMed2003

Intermittent hypoxia increases insulin resistance in genetically obese mice.

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

Adipose Tissue↗
PubMed2003

Tongue neuromuscular and direct hypoglossal nerve stimulation for obstructive sleep apnea.

Recent studies have shown that neuromuscular stimulation of the genioglossus muscle and direct stimulation of the hypoglossal nerve can be performed selectively and safely. Such stimulation, delivered below the arousal threshold, can modulate airflow during sleep in patients with OSA. The feasibility and potential of upper airway stimulation for the treatment of OSA have been demonstrated. Further studies and stimulation-system refinements are presently underway, with hopes of establishing upper airway stimulation as a therapeutic option for this challenging disorder.

Electric Stimulation Therapy↗
PubMed2003

Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea.

Contraction of the genioglossus (GG) has been shown to improve upper airway patency. In the present study, we evaluated responses in upper airway pressure-flow relationships during sleep to electrical stimulation (ES) of the GG in patients with obstructive sleep apnea. Five patients with chronically implanted hypoglossal nerve (HG) electrodes and nine patients with fine-wire electrodes inserted into the GG were studied. Airflow was measured at multiple levels of nasal pressure, and upper airway collapsibility was defined by the nasal pressure below which airflow ceased ["critical" pressure (Pcrit)]. ES shifted the pressure-flow relationships toward higher flow levels in all patients over the entire range of nasal pressure applied. Pcrit decreased similarly during both HG-ES and GG-ES (deltaPcrit was 3.98 +/- 2.31 and 3.18 +/- 1.70 cmH2O, respectively) without a significant change in upstream resistance. The site of collapse (velo- vs. oropharynx) did not influence the response to GG-ES. Moreover, ES-induced reductions in the apnea-hypopnea index of the HG-ES patients were associated with substantial decreases in Pcrit. Our findings imply that responses in apnea severity to HG-ES can be predicted by characterizing the patient's baseline pressure-flow relationships and response to GG-ES.

Adult↗
PubMed2003

A physiologic comparison of nasal and oral positive airway pressure.

STUDY OBJECTIVES: The effectiveness of nasal continuous positive airway pressure (CPAP) in treating obstructive sleep apnea (OSA) is based on raising the intramural pressure above a critical collapsing pressure of the oropharyngeal airway. It is currently unclear whether CPAP delivered orally is also capable of raising pressure in the oropharynx above the critical collapse pressure. DESIGN: We tested a novel oral CPAP device to determine whether the pressure-flow relationships are similar to nasal CPAP and whether the device alters these relationships. Patients were selected based on having moderately severe apnea and were randomized to nasal CPAP, nasal CPAP with oral device, or oral CPAP. SETTING: Johns Hopkins University, The Johns Hopkins Asthma and Allergy Center, Baltimore, MD. PATIENTS: Five men and two women with OSA were studied. INTERVENTIONS: Individual pressure-flow curves were constructed during the application of nasal or oral CPAP. RESULTS: We found the following: (1) a similar effective pressure eliminated inspiratory flow limitation for the nasal or oral CPAP; (2) as pressure in the nose or mouth was lowered below the effective pressure, a linear pressure-flow curve was obtained and a critical closing pressure was described; (3) similar mean (+/- SD) critical pressures of -0.3 +/- 5.3, 1.7 +/- 4.0, and 0.5 +/- 2.8 cm H(2)O, respectively, occurred for nasal CPAP, nasal CPAP with the oral device in place, and oral CPAP conditions (p > 0.1); and (4) the comparable mean values for upstream resistance were 27.8 +/- 19, 19.1 +/- 8.3, and 26.5 +/- 26.7 cm H(2)O/L/s, respectively, for the above three conditions (p > 0.1). CONCLUSIONS: We concluded that comparable upper airway pressure-flow relationships were obtained during oral and nasal breathing. Moreover, effective treatment pressure is obtained when constant pressure is applied through either the nasal or oral route.

Adult↗
PubMed2002

Phenotypic differences in the hemodynamic response during REM sleep in six strains of inbred mice.

The pattern of cardiovascular changes that occur at nighttime can have an impact on morbidity and mortality. Rapid-eye-movement (REM) sleep, in particular, represents a period of increased risk due to marked cardiovascular instability. We hypothesized that genetic differences between inbred strains of mice would affect the phenotypic expression of cardiovascular responses that occur in REM sleep. We monitored polysomnography and arterial blood pressure (P(SA)) simultaneously in six inbred strains of mice as they naturally cycled through sleep/wake states. Two strains elevated their P(SA) above non-REM (NREM) levels for 57.9 +/- 6.6% (BALB/cJ) and 51.8 +/- 8.4% (DBA/2J) of the REM period and exhibited a significant (P < 0.05) number of P(SA) surges greater than 10 mmHg (0.78 +/- 0.36 surges/min for BALB/cJ; 0.63 +/- 0.13 surges/min for DBA/2J). Despite similar P(SA) responses, the DBA/2J strain exhibited a decreased heart rate and the BALB/cJ strain exhibited an increased heart rate during REM sleep. The four other strains (A/J, C57BL/6J, C3H/HeJ, and CBA/J) exhibited a significant hypotensive response associated with no change in heart rate in three of the strains and a significant decrease in heart rate in the A/J strain. The overall variability in P(SA) during REM sleep was significantly greater in the C3H/HeJ strain (26.8 +/- 2.0 mmHg; P < 0.0125) compared with the other five strains. We conclude that genetic background contributes to the magnitude, variability, and arterial baroreceptor buffering capacity of cardiovascular responses during REM sleep.

Animals↗
PubMed2002

The effect of upper airway obstruction and arousal on peripheral arterial tonometry in obstructive sleep apnea.

We evaluated the effects of airflow limitation and arousal on digital vascular tone in 10 patients with obstructive sleep apnea (OSA) using the recently developed, noninvasive technique of peripheral arterial tonometry (PAT). Subjects were maintained at a therapeutic level of continuous positive airway pressure, and nasal pressure was acutely dropped for three to five breaths during nonrapid eye movement sleep over a range of pressures from 9.3 +/- 1.3 to 1.9 +/- 1.3 cm H2O, leading to increasing airway obstruction and decreasing levels of inspiratory airflow. In the absence of a detectable electroencephalographic (EEG) arousal, severe reductions of inspiratory airflow to below 200 ml/second caused significant decreases in PAT amplitude (1.000 +/- 0.007 to 0.869 +/- 0.007 arbitrary units; p < 0.001), whereas mild airflow limitation (> 200 ml/second) had no effect (1.000 +/- 0.009 to 1.011 +/- 0.007 arbitrary units). The presence of an EEG arousal accentuated the response to airflow obstruction, such that the PAT amplitude decreased more (p < 0.001) in the presence of arousal (1.000 +/- 0.007 to 0.767 +/- 0.010 arbitrary units) than in the absence of arousal (1.000 +/- 0.007 to 0.923 +/- 0.007 arbitrary units). We conclude that airflow obstruction in patients with OSA causes an acute digital vasoconstriction that is accentuated in the presence of an EEG arousal.

Adult↗
PubMed2002

The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep.

BACKGROUND: Daytime sleepiness is common in patients with sleep-disordered breathing. Although respiratory events during sleep are associated with the occurrence of daytime sleepiness, the differential impact of these events during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep on daytime sleepiness has not been well characterized. STUDY OBJECTIVES: To determine the effect of respiratory events during REM sleep and NREM sleep on daytime sleepiness, as assessed by the multiple sleep latency test (MSLT). DESIGN: Cross-sectional study. SETTING: University-based sleep disorders laboratory. PARTICIPANTS: Patients referred for polysomnography and daytime MSLT (n=1,821). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The study sample was initially divided into quartiles based on the level of the apnea-hypopnea index (AHI) during NREM sleep. Within the first NREM-AHI quartile (NREM-AHI < 8.3 events/hr), the association between REM-related respiratory events and daytime sleepiness was examined using the method of Kaplan-Meier analysis and Cox proportional hazards regression. After adjusting for age, gender, body mass index, and the duration of NREM and REM sleep, REM-AHI was not associated with daytime sleepiness (Relative Risk: 1.01; 95%CI: 0.94-1.10). Similarly, no significant association was observed between REM-AHI and the MSLT in patients within the second through fourth NREM-AHI quartiles. In contrast, increasing severity of disordered breathing during NREM sleep was associated with daytime sleepiness. For a 10-point increase in NREM-AHI, the adjusted relative risks for daytime sleepiness in the second through fourth NREM-AHI quartile were 1.21 (95%CI: 1.01-1.46), 1.20 (95%CI: 1.05-1.37), and 1.10 (95%CI: 1.04-1.16), respectively. CONCLUSION: Sleep-disordered breathing during NREM sleep, but not REM sleep, is associated with increased risk of daytime sleepiness.

Adult↗