Obstructive Sleep Apnea, Gender Biology, and Autonomic Regulation

Summary

Principal Investigator: PAUL MICHAEL MACEY
Abstract: DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) occurs in close to 20% of men and 10% of women in the adult population, and is an independent risk factor for cardiovascular disease and death. Despite the lower prevalence in women, female OSA patients show more severe cardiovascular and neuropsychological consequences than men with the disorder. The causes of the health problems associated with OSA are unclear, and there are few clinical guidelines for treating symptoms other breathing support with positive airway pressure (PAP);that support assists ventilation, but does little to restore sympathetic dysfunction, one factor that likely contributes to hypertension and other cardiovascular sequelae in the syndrome. Since sympathetic outflow is regulated by the brain, a possible contribution to the cardiovascular sequelae is impaired regulation due to neural injury from the intermittent hypoxia and other characteristics of OSA. We showed such injury in OSA together with deficient cardiovascular control in many brain regions, including the insular cortex, an area that integrates higher brain processing and sensory input to modulate brainstem and hypothalamic autonomic outflow. Our R21 data show that female OSA patients have an even greater extent of insular cortex injury and dysfunction than male OSA patients. We therefore hypothesize that in OSA patients, the insular cortex has impaired function due to injury, resulting in less effective cardiovascular regulation, and these effects are especially severe in female OSA patients. We will evaluate brain structure with diffusion tensor imaging, brain function with functional magneti resonance imaging (fMRI), and cardiovascular function with heart rate measurements during three autonomic challenges, an inspiratory apnea, Valsalva maneuver, and static hand grip. We will localize the insular cortex subdivisions involved in sympathetic modulation from high-resolution MRI scans. We will study 144 people across four age-matched groups: newly-diagnosed OSA females and males matched for disease severity, and healthy control females and males. Females will be assessed for menopausal and hormonal status, with the aim of balancing the numbers of pre- and post-menopausal women, and including hormonal factors in statistical models. In males and females, the findings will show whether disrupted neural regulation of sympathetic activity occurs in OSA, whether that dysfunction is paralleled by brain injury, and whether cardiovascular responsiveness is also impaired. We will also perform an exploratory assessment of the effects of 3 months of PAP treatment on autonomic function in 15 male and 15 female patients, and gather evidence as to whether autonomic central function can recover, at least in the short term. A lack of recovery would suggest additional treatments to PAP should be investigated. Findings of worse effects of OSA in women would highlight the need to broaden OSA treatment, which currently solely focuses on resolving breathing disruptions for moderate and severe OSA, and is typically ignored in mild OSA in women, despite evidence that mild OSA in females is accompanied by severe cardiovascular characteristics.
Funding Period: 2013-06-01 - 2018-03-31
more information: NIH RePORT

Top Publications

  1. pmc Sleep-disordered breathing: effects on brain structure and function
    Ronald M Harper
    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA Brain Research Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA Electronic address
    Respir Physiol Neurobiol 188:383-91. 2013
  2. pmc Regional cerebral blood flow alterations in obstructive sleep apnea
    Santosh K Yadav
    Department of Neurobiology, University of California at Los Angeles, Los Angeles, CA 90095, USA
    Neurosci Lett 555:159-64. 2013
  3. pmc Heart rate responses to autonomic challenges in obstructive sleep apnea
    Paul M Macey
    University of California at Los Angeles School of Nursing, University of California Los Angeles, Los Angeles, California, United States of America Brain Research Institute, David Geffen School of Medicine at University of California Los Angeles, University of California Los Angeles, Los Angeles, California, United States of America
    PLoS ONE 8:e76631. 2013
  4. pmc Accelerated echo-planar J-resolved spectroscopic imaging in the human brain using compressed sensing: a pilot validation in obstructive sleep apnea
    M K Sarma
    From the Departments of Radiological Sciences M K S, R N, R K, J P V, J F, M A T
    AJNR Am J Neuroradiol 35:S81-9. 2014

Detail Information

Publications4

  1. pmc Sleep-disordered breathing: effects on brain structure and function
    Ronald M Harper
    Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA Brain Research Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA Electronic address
    Respir Physiol Neurobiol 188:383-91. 2013
    ..Sleep-disordered breathing should be viewed as a condition that includes central nervous system injury and impaired function; the processes underlying injury remain unclear. ..
  2. pmc Regional cerebral blood flow alterations in obstructive sleep apnea
    Santosh K Yadav
    Department of Neurobiology, University of California at Los Angeles, Los Angeles, CA 90095, USA
    Neurosci Lett 555:159-64. 2013
    ..The asymmetric CBF declines in motor regulatory areas may contribute to loss of coordination between upper airway and diaphragmatic musculature, and lead to further damage in the syndrome. ..
  3. pmc Heart rate responses to autonomic challenges in obstructive sleep apnea
    Paul M Macey
    University of California at Los Angeles School of Nursing, University of California Los Angeles, Los Angeles, California, United States of America Brain Research Institute, David Geffen School of Medicine at University of California Los Angeles, University of California Los Angeles, Los Angeles, California, United States of America
    PLoS ONE 8:e76631. 2013
    ..The dysfunctions may reflect central injury in the syndrome, and suggest autonomic deficiencies that may contribute to further tissue and functional pathologies...
  4. pmc Accelerated echo-planar J-resolved spectroscopic imaging in the human brain using compressed sensing: a pilot validation in obstructive sleep apnea
    M K Sarma
    From the Departments of Radiological Sciences M K S, R N, R K, J P V, J F, M A T
    AJNR Am J Neuroradiol 35:S81-9. 2014
    ....

Research Grants30

  1. Role of Sphingolipids in the Pathobiology of Lung Injury
    Viswanathan Natarajan; Fiscal Year: 2013
    ..Together, this PPG addresses critical needs (insights, biomarkers, therapies) in ALI and RILI facilitating development of pharmacogenomic assays and SIP-based therapies for inflammatory lung injury. ..
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  3. Cannabimimetic Treatment of Obstructive Sleep Apnea: A Proof of Concept Trial
    Phyllis C Zee; Fiscal Year: 2013
    ..By providing a path toward the first viable OSA pharmacotherapeutic, the proposed studies could have a tremendous impact on clinical practice. ..
  4. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  5. A randomized trial of bariatric surgery for the treatment of sleep apnea
    Sanjay R Patel; Fiscal Year: 2013
    ..In this study, we will conduct a trial comparing the ability of CPAP and bariatric surgery to treat sleep apnea in patients who have severe sleep apnea and morbid obesity. ..
  6. Carotid afferent and parafacial neuronal excitatory effects on breathing
    Hubert V Forster; Fiscal Year: 2013
    ..Validation of this hypothesis will indicate the major pathway (Res. Plan, Figure 1, page 1) for central mediation of carotid afferent excitatory effect is through the pFRG/RTN. ..
  7. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
  8. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  9. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  10. Center for Biomedical Research Excellence in Pathogen-Host Interactions
    Stephen B Pruett; Fiscal Year: 2013
    ..We expect the combined reductionist and global approach in this COBRE to produce significant progress in research on these pathogens. ..
  11. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  12. Molecular and Cellular Therapies for Muscular Dystrophy
    Stanley C Froehner; Fiscal Year: 2013
    ..The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories. ..
  13. Cell Characterization and Imaging for Regenerative Therapies in Ischemic Diseases
    PHILLIP CHUNG MING YANG; Fiscal Year: 2013
    ..We intend to correlate these subsets with clinical endpoints in our PAD and CAD research protocols, to determine what cell subsets may be most critical for any observed benefit. ..
  14. Autonomic and Antihypertensive Actions of Neuronal CGRP/RAMP1 Receptors
    Mark W Chapleau; Fiscal Year: 2013
    ..Inhibition of Ang II-mediated effects by activation of CGRP/RAMP1 receptors has widespread implications in hypertension and heart failure. ..
  15. Sleep Disordered Breathing and Passive Limb Movement in Children with Paraplegia
    Marlyn Woo; Fiscal Year: 2013
    ....