Harly Greenberg

Chronic-intermittent hypoxia: a model of sympathetic activation in the rat

This review focuses upon the development of a small animal model that incorporates exposure to chronic-intermittent hypoxia to produce systemic hypertension similar to that experienced by humans with the obstructive sleep apnea syndrome. It has been suggested that experimentally-induced hypertension, like human hypertension, is due to activation of the sympathetic nervous system. That hypothesis is supported by physiological studies carried out in humans with obstructive sleep apnea as well as in animals exposed to chronic-intermittent hypoxia. Furthermore, recent anatomical studies of exposed animals strongly suggested that activation was widespread and included cortical and brainstem components of the sympathetic system. Such findings, while illustrating the complexity of modeling human disease in animals, also demonstrate the heuristic value of chronic-intermittent hypoxia as an experimental approach.

Expression of c-fos in the rat brainstem after chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) may cause sustained systemic hypertension by increasing sympathetic neural discharge (SND). We hypothesized that CIH alters brainstem circuits modulating SND. After 30 days of CIH exposure in rats, increased c-fos labeling was seen in the nucleus of the solitary tract and ventrolateral medulla as well as other brainstem regions involved in regulation of SND. Increased expression of c-fos after CIH may indicate changes in neuronal genetic transcription which ultimately modulate SND.

Chronic-intermittent hypoxia induces immediate early gene expression in the midline thalamus and epithalamus

Chronic-intermittent hypoxia (CIH) was postulated to activate thalamic regions that are synaptically related to autonomic-related areas of the cerebral cortex. Animals exposed to CIH for 30 days exhibited c-fos labeling in paraventricular thalamic and lateral habenular nuclei. Our findings strongly suggest activation of a diencephalic network that participates in behavioral responses to chronic stress.

Immediate-early gene expression in cerebral cortex following exposure to chronic-intermittent hypoxia

Chronic-intermittent hypoxia (CIH) was postulated to evoke c-fos expression in cortical regions that modulate sympathetic discharge. Animals exposed to CIH for 30 days exhibited c-fos labeling in medial prefrontal, cingulate, retrosplenial, and insular cortices. Our findings strongly suggest activation of cortical circuits that adaptively regulate sympathetic and cardiovascular activities.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is prevalent with type 2 diabetes. Conversely, nondiabetic patients with OSA are at increased risk of developing insulin resistance and diabetes. These disorders independently contribute to increased cardiovascular and cerebrovascular morbidity and mortality. The pathophysiology of OSA may help explain these associations. Evidence demonstrates that treatment of OSA with continuous positive airway pressure may lead to improvement in insulin sensitivity, hemoglobin A1c, systemic hypertension, and other components of the metabolic syndrome. Recognizing and treating OSA in patients with insulin resistance or diabetes ameliorates OSA-related symptoms and improves cardiometabolic risk.

Disparities in Obstructive Sleep Apnea and Its Management between a Minority-Serving Institution and a Voluntary Hospital

We assessed disparities in severity of obstructive sleep apnea (OSA) and associated comorbidities, as well as in provision of sleep medicine health care, between patients evaluated for OSA in a voluntary hospital (VH) primarily serving a middle-class population with health-care insurance and a city hospital-based minority-serving institution (MSI) largely treating lower income, uninsured, and indigent patients. A retrospective chart review of patients evaluated for OSA at the VH (n= 200) and at the MSI (n= 103) was performed. Despite similar age and apnea hypopnea index, MSI patients had a greater body mass index, higher daytime systemic blood pressure, more comorbid medical conditions, and a lower minimum sleep SaO2than VH patients. Systemic hypertension, diabetes mellitus, asthma, and congestive heart failure were more prevalent in the MSI group. Forty-two percent of the MSI patients diagnosed with OSA failed to follow up for treatment compared with 7% in the VH group, p< 0.001. Disparities in OSA-associated comorbid conditions, as well as in delivery of sleep medicine-related health care, were evident between the VH and MSI groups. These findings suggest that OSA may be an important factor contributing to socioeconomic-based differences in morbidity and mortality.

Role of hypoxemia and hypercapnia in acute cardiovascular response to periodic apneas in sedated pigs

The effects of hypoxemia and hypercapnia in acute cardiovascular response to periodic non-obstructive apneas were explored in seven preinstrumented, sedated paralyzed and ventilated pigs under three conditions: room air breathing (RA), O2 supplementation (O2), and supplementation with O2 and CO2 (CO2). EEG monitoring showed no arousal under any conditions. RA apneas increased mean arterial pressure (MAP, from baseline 95.9 +/- 4.5 to late apnea 124.4 +/- 7.8 Torr, P < 0.01), left ventricular end-diastolic pressure, end-diastolic and end-systolic myocardial fiber lengths and systemic vascular resistance, but decreased cardiac output (CO, 3.09 +/- 0.34-2.37 +/- 0.26 L/min, P < 0.01), heart rate (HR, 115.1 +/- 7.5-102.0 +/- 7.8 bpm, P < 0.01), and stroke volume (SV, 29.6 +/- 0.7 21.1 +/- 1.8 ml, P < 0.01). 02 apneas produced similar decreases in HR (114.0 +/- 11.8-105.4 +/- 8.7 bpm, P < 0.05) as with RA apneas, but smaller increases in MAP (94.5 +/- 1.8-103.4 +/- 2.8 Torr, P < 0.01) and in the variables of pre- and after-load. CO and SV remained unchanged with O2 apneas. CO2 was associated with higher MAP, CO, and HR at baseline relative to RA, but similar cardiovascular response during apneas in direction and magnitude to those of O2 apneas. We conclude that in this model hypoxemia is a major but not the sole determinant of the pressor response during apneas. Hypercapnia cannot explain the pressor response seen when hypoxemia is abolished. The HR fall during apneas is independent of hypoxemia, hypercapnia and the pressor response.

Differing effects of the anxiolytic agents buspirone and diazepam on control of breathing

We compared ventilatory effects of the nonsedating anxiolytic buspirone with those of the sedating anxiolytic diazepam in nine normal men. Resting ventilatory parameters and ventilatory responses to CO2 rebreathing and inspiratory threshold loading were measured before and after placebo, diazepam, and buspirone. Placebo had no ventilatory effects. Diazepam had no effect on resting ventilation but depressed response to CO2. Buspirone had no effect on resting ventilation or CO2 response. During loading, buspirone did not alter the augmentation of mouth pressure; diazepam produced a trend toward less augmentation. Both anxiolytics altered the load compensation response for the group; in particular, an increase in ventilation during loading (seen in three of nine subjects) was suppressed by drug administration. Diazepam also markedly depressed one subjects loaded ventilation below unloaded ventilation. In summary, buspirone did not cause the depression of respiratory center chemosensitivity that was seen with diazepam and produced less depression of load compensation in normal subjects. This suggests that it may be a safer anxiolytic in patients with lung disease.

γ-Aminobutyric acid contributes to modulation of cardiorespiratory control after chronic ventilatory loading

Diseases imposing chronic ventilatory loads may depress ventilation and cause chronic hypercapnia. This may be a result of mechanical loading imposed on pre-existing decreased respiratory drive or functional alteration of neural circuits involved in ventilatory control. To evaluate these possibilities, chronic resistive airway loading was imposed in rats via a circumferential tracheal band which tripled tracheal resistance (obstructed group). Sham surgery was performed in controls. After 8 weeks, animals were anesthetized (urethane) and tracheostomy performed relieving increased tracheal resistance. The ventral medullary surface (VMS) was exposed and the intermediate area (IA) identified. The integrated diaphragm EMG (EMGDI) was recorded. The obstructed group was hypercapnic while controls were eucapnic (PCO2, 45.1 +/- 7.9 vs. 37.6 +/- 3.4 Torr; P < 0.001). Respiratory rate (RR) remained lower in obstructed than in control animals despite relief of the resistive load by tracheostomy (58.5 +/- 5.1 vs. 75.4 +/- 5.4 bpm; P < 0.05). Application of 1 mM bicuculline soaked pledgets (BIC) to the IA of the VMS significantly increased EMGDI in obstructed but not in control animals (27.5 +/- 5.5 vs. 5.2 +/- 4.4%; P < 0.006). RR was unaffected. Mean arterial pressure increased with BIC in obstructed but not control animals (23.0 +/- 6.5 vs. 4.5 +/- 3.5%; P < 0.02). These data suggest that alteration of cardiorespiratory control occurs during chronic resistive hypercapnic loading and that GABAergic neurons in the VMS participate in this adaptive response.

Congestive heart failure and sleep apnoea—possible mechanisms and effect of CPAP therapy

SUMMARY  Sleep‐disordered breathing has been associated with increased cardiovascular morbidity and mortality. However, despite several plausible mechanisms whereby obstructive sleep apnoea might be associated with left ventricular dysfunction and congestive heart failure, only limited data exist linking those disorders. These studies are reviewed along with possible mechanisms leading to left ventricular dysfunction in obstructive sleep apnoea. Recent investigations demonstrating improvement in left ventricular function after CPAP therapy in patients with congestive heart failure are reviewed as well. Finally, new data are presented from an animal model of congestive heart failure demonstrating a beneficial effect of CPAP on cardiac index in association with a decline in systematic vascular resistance. Remarkably, these effects persisted even after CPAP was removed. Possible mechanisms whereby CPAP may lead to improvement in cardiac output are discussed.