OBSTRUCTIVE SLEEP APNEA INCREASES CARDIOVASCULAR RISK IN TYPE 2 DIABETES
Malhotra Atul
Beth Israel Deaconess Medical Centercity: Boston country: United States (us)
Grant 1R01HL110350-01A1 from National Heart, Lung, And Blood Institute
Abstract: Despite improvements in the management of cardiovascular disease in type 2 diabetes, its prevalence remain still unacceptably high while numerous recent studies have indicated that improvements of glycemic control beyond a certain point have minimal, if any, effects on the macrovascular disease. This has led to the suggestion that targeting coexisting conditions, such as OSA, may be the new frontier in the effort to reduce risk of cardiovascular disease in diabetes. OSA was initially thought to be a marker of comorbidities related to an unfit lifestyle but is currently considered a real vascular risk factor. Thus, both animal and human epidemiological and interventional studies have shown that OSA can lead to development of cardiovascular disease. There is also a strong possibility that a synergistic interaction exists between OSA and diabetes significantly increasing cardiovascular risk, but before solid conclusions can be reached, the alternative hypothesis, namely that two diseases may offset one another or that risk may be limited by ceiling effects of the two diseases should be explored in more detail. The main hypothesis of the current application is that OSA and diabetes additively or synergistically increase the proinflammatory state that leads to endothelial dysfunction and the development of cardiovascular disease. We also hypothesize that appropriate treatment of OSA will improve vascular function in both the micro- and macrocirculation. Finally, we will test the hypothesis that this improvement is associated with a reduction of the proinflammatory state. In order to test our hypothesis, we will prospectively examine the effect of OSA treatment in the vascular function and the proinflammatory state of patients with DM and OSA. In order to test our hypothesis, the study will have three aims. The first aim will establish the combined effect of OSA and DM on cardiovascular function by comparing the effects of DM, OSA, and DM plus OSA on the ventricular function, aortic elasticity, vascular reactivity and proinflammatory status. The second aim involves a prospective, randomized clinical trial which will examine the effect of nasal continuous positive airway pressure (CPAP) treatment on the cardiovascular risk. The third aim will identify possible mechanisms through which OSA treatment reduces cardiovascular risk. The current proposal will encompass the collaboration of investigators working in various disciplines and has the potential to create very strong synergy and will lead to the generation of novel and very clinically useful data. Thus, it will be one of the very first ones in providing insight regarding the contributory effects of OSA in vascular disease in T2DM and the possible beneficial effects of OSA treatment. In that sense, it can have an immediate clinical effect as it may represent as paradigm shift in the way that OSA is viewed and managed by the professionals who treat T2DM patients. In addition, the proposed mechanistic studies have the potential to lead to new therapeutic approaches in the management of T2DM patients with OSA. A strong synergistic interaction exists between OSA and diabetes significantly increasing cardiovascular risk, but before solid conclusions can be reached, the alternative hypothesis, namely that two diseases may offset one another or that risk may be limited by ceiling effects of the two diseases should be explored in more detail. We will establish the combined effect of OSA and DM on cardiovascular function by comparing the effects of DM, OSA, and DM plus OSA on the ventricular function, aortic elasticity, vascular reactivity and proinflammatory status. We will also investigate the effect of OSA treatment in the vascular function and the proinflammatory state of patients with DM and OSA
Keywords: Animals; Blood Pressure; Blood Vessels; brachial artery; Cardiovascular Diseases; cardiovascular disorder risk; Cardiovascular Physiology; cardiovascular risk factor; Cardiovascular system; clinical effect; Clinical Trials; Collaborations; Comorbidity; Data; Development; Diabetes Mellitus; Discipline; Disease; Double-Blind Method; Elasticity; Epidemiology; frontier; Functional disorder; Generations; glycemic control; Human; improved; insight; Iontophoresis; Lead; Life Style; Lipids; macrovascular disease; Magnetic Resonance Imaging; Mediating; Microcirculation; nCPAP Ventilation; Neurocognitive; nitrosative stress; Non-Insulin-Dependent Diabetes Mellitus; novel; novel therapeutic intervention; Obesity; Obstructive Sleep Apnea; Patients; Poly(ADP-ribose) Polymerases; Prevalence; primary outcome; prospective; public health medicine (field); Randomized; Randomized Clinical Trials; Research Design; Research Personnel; Risk; Risk Factors; Role; Skin; Solid; Suggestion; Techniques; Testing; Ultrasonography; Vascular Diseases; Ventricular Function; Work
Relevance: A strong synergistic interaction exists between OSA and diabetes significantly increasing cardiovascular risk, but before solid conclusions can be reached, the alternative hypothesis, namely that two diseases may offset one another or that risk may be limited by ceiling effects of the two diseases should be explored in more detail. We will establish the combined effect of OSA and DM on cardiovascular function by comparing the effects of DM, OSA, and DM plus OSA on the ventricular function, aortic elasticity, vascular reactivity and proinflammatory status. We will also investigate the effect of OSA treatment in the vascular function and the proinflammatory state of patients with DM and OSA
Project start date: 2011-12-01
Project end date: 2016-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
1R01HL110350-01A1 (2012): $871207
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Malhotra Atul
MECHANISMS UNDERLYING THE AGING PREDISPOSITION TO OBSTRUCTIVE SLEEP APNEA
Malhotra Atul, Medical Director, Sleep Disorders Progra
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Grant 5R01HL090897-03 from National Heart, Lung, And Blood Institute
Abstract: Obstructive sleep apnea is a major problem in the elderly due to its high prevalence and its well recognized neurocognitive and cardiovascular complications. Afflicted individuals have substantial daytime symptoms including fatigue, malaise, sleepiness and reduced quality of life. Despite this, minimal research has been performed to investigate the mechanisms underlying the development of this disease with aging. Current theory suggests that sleep apnea pathogenesis involves a complex interactions of anatomical variables, protective reflex mechanisms, ventilatory control abnormalities among others. The principal investigator proposes to extend the observations from his Beeson award to pursue more comprehensive evaluations of the critical variables using a new patient population in both sleep and wakefulness. During the proposed granting period, we will investigate the normal effects of aging on a number of mechanistic variables of interest and further we will define the impact of sleep apnea disease on these parameters. Based on our preliminary data, the groups of variables will likely form phenotypic clusters whereby a certain abnormality (or group of abnormalities) either causes disease (or protects from disease) in older and younger individuals. This protocol will allow us to test a number of hypotheses regarding potential mechanisms underlying sleep apnea using state-of-the-art technology and methods. We have developed a conceptual framework whereby we can classify patients into OSA or control based on their underlying pathophysiology with a view towards understand why a given patient does or does not have sleep apnea. Ultimately our goal is to identify new therapeutic targets for sleep apnea in the elderly since the current therapies are often poorly tolerated in this and other age groups. Sleep apnea is a major problem for the elderly because it is very common and leads to marked reductions in quality of life. Treatments for sleep apnea are often poorly tolerated by older individuals and therefore research into underlying mechanisms is very important in order for new treatments to be developed. We plan to characterize many of the variables important in causing sleep apnea so that we can develop a better understanding of why the elderly develop this disease, and how best to prevent or minimize its complications
Keywords: Age; age effect; age group; Aging; Airway Resistance; Anatomy; Apnea; Arousal; Attenuated; Award; base; Breathing; burden of illness; cardiovascular risk factor; Cardiovascular system; Categories; cerebrovascular; Complex; Data; Dependence; Deposition; design; Deterioration; Development; Dilator; Disease; Dropout; Elderly; Enrollment; Environmental air flow; Evaluation; Event; Excessive Daytime Sleepiness; experience; Failure (biologic function); falls; Fatigue; Fatty acid glycerol esters; Functional disorder; Goals; Grant; High Prevalence; Hypertension; Hypoxemia; Image; indexing; Individual; instrumentation; interest; Left; Literature; Lung; lung volume; Magnetic Resonance Imaging; Malaise; Measures; Mechanics; Mediating; men; Mental Depression; Methodology; Methods; Minor; Modeling; motor control; Motor Vehicles; Muscle; Muscle function; muscle strength; Myocardial Infarction; Myopathy; Nature; Neurocognitive; neuromuscular; Neuropathy; new therapeutic target; normal aging; Obstructive Sleep Apnea; older patient; Outcome Measure; Output; Participant; Pathogenesis; patient population; Patients; Pattern; Performance; pharyngeal critical pressure; Phenotype; Play; Population; Predisposing Factor; Predisposition; pressure; Prevalence; prevent; Principal Investigator; Protocols documentation; public health relevance; Publishing; Pulmonary Hypertension; Quality of life; Recruitment Activity; Recurrence; Reflex action; relating to nervous system; Research; Rest; Risk; Role; Selection Bias; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Fragmentations; sleep onset; Sleep Stages; Stimulus; stroke; Structure; success; Symptoms; Techniques; Technology; Testing; theories; Time; Traction; Vitelliform macular dystrophy; volunteer; Wakefulness; Woman; Work
Relevance: Sleep apnea is a major problem for the elderly because it is very common and leads to marked reductions in quality of life. Treatments for sleep apnea are often poorly tolerated by older individuals and therefore research into underlying mechanisms is very important in order for new treatments to be developed. We plan to characterize many of the variables important in causing sleep apnea so that we can develop a better understanding of why the elderly develop this disease, and how best to prevent or minimize its complications
Project start date: 2009-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01HL090897-03 (2011): $445938
SINGLE MOTOR UNIT GENIOGLOSSUS RECORDINGS TO UNDERSTAND SLEEP APNEA PATHOGENESIS
Malhotra Atul, Medical Director, Sleep Disorders Progra
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Grant 5R01HL085188-04 from National Heart, Lung, And Blood Institute
Abstract: Obstructive sleep apnea (OSA) is a very common disease with major health consequences. The fundamental problem leading to OSA is a failure of the neural control of the upper airway muscles during sleep in those anatomically predisposed. Some progress has been made in the understanding of the mechanisms underlying OSA by performing multi-unit electromyography recordings on upper airway dilator muscles such as the genioglossus (GG). Although these studies have been useful in establishing the importance of these muscles in protecting upper airway patency, and the potential stimuli of importance, we still have a relatively cursory understanding of apnea pathogenesis. Using a newer technique in this area, we are now actively recording single motor units (SMUs) in order to establish the characteristics of the various components contributing to overall genioglossus activity. We have characterized six different SMU patterns of genioglossus firing, some with activity predominantly during inspiration, some with constant activity throughout the respiratory cycle, and some with various combinations. Of note these various SMUs appear to have different response characteristics from standpoint of their activity, for example in going from wakefulness to sleep. Similarly, the response of these various SMUs to standard respiratory stimuli appears to be quite different. Specifically, the change in behavior of SMUs in the transitions from wakefulness to sleep is predicated on the discharge pattern during prior wakefulness. We have also observed major differences in SMUs in OSA patients compared to controls and during REM sleep. Also, certain types of motor units appear to be critically involved in the development of upper airway collapse. Based on animal and human data, we are in the process of developing a working neurobiological model to understand the major pathways regulating GG activity, and how these may be dysfunctional in OSA. We therefore strongly believe that the detailed characterization of SMUs in normal subjects and OSA patients and how SMU behavior changes from wakefulness to NREM and REM sleep will lead to major advances in our understanding of apnea pathogenesis. Ultimately, the development of this working model of upper airway motor control, and the characterization of the muscle control abnormalities in OSA will facilitate the identification of therapeutic targets for the treatment of OSA. PUBLIC HEALTH RELEVANCE. Obstructive sleep apnea is a highly prevalent and debilitating disease with well established consequences to the brain and cardiovascular system. Current understanding of why sleep apnea occurs is incomplete, although the control of upper airway dilator muscles such as the genioglossus are thought to be important. Single motor unit technology allows scientists to understand the various different groups of neurons that are controlling the muscle and to draw inferences regarding how these neurons are being controlled; such studies will be critical for new treatments for this condition to emerge, such as drug treatment of sleep apnea
Keywords: Affect; animal data; Animals; Apnea; Area; Arousal; base; Behavior; behavior change; Behavioral; Brain; Breathing; Carbon Dioxide; Cardiovascular system; Cell Nucleus; Characteristics; Chemical Stimulation; Data; Deglutition; Development; Dilator; Disease; Drops; Electromyography; Environmental air flow; Exhalation; Failure (biologic function); falls; Health; Human; human data; Hypercapnia; hypoglossal nucleus; improved; Individual; insight; Iron; Lead; Lung; Mechanical Stimulation; Mechanics; Methods; Modeling; Motor; motor control; Muscle; Neurobiology; Neurocognitive; Neurons; neuroregulation; new therapeutic target; novel strategies; Obstructive Sleep Apnea; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phase; pressure; Process; Recruitment Activity; relating to nervous system; REM Sleep; Research; research study; respiratory; response; Role; Scientist; Sleep; Sleep Apnea Syndromes; sleep onset; Source; Stimulus; Techniques; Technology; therapeutic target; Tongue; Wakefulness; Withdrawal; Work
Project start date: 2008-09-15
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01HL085188-04 (2011): $387855
AROUSAL THRESHOLD IN THE PATHOGENESIS OF OBSTRUCTIVE SLEEP APNEA
Malhotra Atul, Medical Director, Sleep Disorders Progra
Beth Israel Deaconess Medical Centercity: Boston country: United States (us)
Abstract: Obstructive sleep apnea (OSA) is a highly prevalent condition with major neurocognitive and cardiovascular sequelae. Despite its recognized consequences, the treatment of this condition remains unacceptable as the existing therapies are poorly tolerated and/or have highly variable efficacy. The role of the arousal threshold has received minimal attention in the OSA literature; despite recent recognition that the propensity to wake up from sleep may have a major pathophysiological role is OSA. The accumulation of respiratory stimuli during sleep can activate upper ainway muscles to preserve pharyngeal patency, but can only do so if sufficient time is available for 002 and negative pressure to develop. That is, premature awakening could lead to recurrent arousals and prevent the stabilization of pharyngeal patency during sleep. The present application will study differences in arousal threshold between OSA and matched controls (Aim 1), and the reversibility of abnormalities in OSA with CPAP therapy (Aim 2). The role of non-myorelaxant hypnotic therapy will also be assessed from standpoint of the effects on upper ainway mechanics and control (Aim 3) and therapeutic effects on short-term clinical outcome (Aim 4). Our research will interact heavily with all of the other Projects within this PPG by providing clinical relevance to the basic research regarding the role of the parabrachial complex on arousal from sleep. In addition, the proposed rodent experiments by our collaborators will provide mechanistic insights into the arousal response which would involve studies neither feasible nor ethical in humans. Project 2 will therefore define the potential role of the arousal threshold in OSA pathogenesis and its viability as a therapeutic target in OSA, at least for a subgroup of patients
Keywords: 1, 2, 4-Triazolo(4, 3-a)pyridin-3(2H)-one, 2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-; Acoustic; Acoustics; Adherence; Adherence (attribute); Advocate; Affect; Apnea; Apnea, Sleep; Apoplexy; Arousal; Aspiration, Mechanical; Aspiration, Respiratory; Attention; base; Basic Research; Basic Science; Blood Pressure, High; brain attack; Brain Stem; Brainstem; Breathing; Carbon Dioxide; carbon dioxide retention; Carbon dioxide, increased level; Carbonic Anhydride; Cardiovascular; Cardiovascular Body System; cardiovascular risk; cardiovascular risk factor; Cardiovascular system; Cardiovascular system (all sites); Catecholamines; Cerebral Stroke; cerebral vascular accident; Cerebrovascular accident; Cerebrovascular Apoplexy; Cerebrovascular Stroke; circulatory system; Clinical; clinical investigation; clinical relevance; Clinical Trials; Clinical Trials, Unspecified; clinically relevant; CO2; cognitive function; Complex; Continuous Positive Airway Pressure; CPAP; CPAP Ventilation; craniofacial; craniofacies; Data; Deposit; Deposition; Dilator; Disease; disease/disorder; Disorder; Drainage, Suction; dreaming sleep; EEG; Electroencephalography; elevated carbon dioxide; esophageal pressure; esophagus pressure; Ethics; Event; experiment; experimental research; experimental study; falls; Fats; Fatty acid glycerol esters; Female; gender difference; Goals; heavy metal lead; heavy metal Pb; High Prevalence; Human; human subject; Human, General; Hypercapnia; hypercarbia; hyperpiesia; hyperpiesis; Hypertension; hypertensive disease; hypnotic; Hypoxemia; hypoxemic; Impairment; improved; Individual; Inhalation; Inhaling; insight; inspiration; Inspiration, Respiratory; Lead; Literature; Logic; male; Mammals, Rodents; Man (Taxonomy); Man, Modern; Mechanics; men; men`s; mid life; mid-life; middle age; middle aged; midlife; Motor carrier accident; motor vehicle accident; Muscle; Muscle function; Muscle structure of pharynx; Muscle Tissue; Neurocognitive; new therapeutic target; Obstructive Sleep Apnea; onset of sleep; Organ; Organ System, Cardiovascular; Outcome; Paradoxical Sleep; Pathogenesis; Patients; Pattern; Pb element; Persons; Pharyngeal Muscles; Physiologic; Physiological; Predisposition; premature; pressure; Pressure; Pressure- physical agent; Prevalence; prevent; preventing; Pulmonary Body System; Pulmonary Organ System; rapid eye movement sleep; recruit; Recruitment Activity; Recurrence; Recurrent; Reflex; Reflex action; Regulation; REM Sleep; Reporting; Research; research study; respiratory; respiratory reflex; Respiratory System; Respiratory system (all sites); respiratory tract; response; Rhombencephalic Sleep; Rodent; Rodentia; Rodentias; Role; Science of Statistics; Severities; sex; Sex Characteristics; Sex Differences; sexual dimorphism (noncellular); Sleep; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Sleep Hypopnea; sleep onset; Sleep, Fast-Wave; Sleep, REM; Sleep-Disordered Breathing; social role; Staging; Statistics; statistics; Stimulus; Stroke; stroke; Structure; SUBGP; Subgroup; Suction; Susceptibility; Sympathins; Syndrome, Sleep Apnea, Obstructive; Testing; theories; Therapeutic Effect; therapeutic target; Time; Tradozone; Trazodone; Vascular Accident, Brain; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vascular, Heart; vehicular accident; Wakefulness; Wakefulnesses; Woman
Relevance: Obstructive sleep apnea is strongly implicated in motor vehicle accidents as well as high blood pressure and stroke. How easily an individual wakes up from sleep (arousal threshold) is something that may be important in why sleep apnea occurs. We propose studies that will examine the role of the arousal threshold with an ultimate goal of developing new treatments for sleep apnea to prevent its serious complications
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5P01HL095491-02_8192 (2011): $299536
ASSESSMENT OF UPPER AIRWAY MECHANICS USING NEWER EMG TECHNIQUES
Malhotra Atul, Medical Director, Sleep Disorders Progra
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Grant 5K24HL093218-03 from National Heart, Lung, And Blood Institute
Abstract: Immediate goals To apply newer electromyographic techniques to upper airway muscles with a view towards identifying important therapeutic targets in obstructive sleep apnea. Career development goals To provide sufficient time for mentoring of trainees and research activities. Research project Obstructive sleep apnea is an important disease due to its high prevalence and well established neurocognitive and cardiovascular sequelae. Treatment of this disease remains problematic since the existing therapies are either poorly tolerated or have variable efficacy, leading many to advocate for further research into underlying mechanisms. Prior research has established in the importance of the upper airway muscles (such as the genioglossus and tensor palatini) in the pathogenesis of sleep apnea. However, multi-unit electromyographic recordings provide an average representation of innumerable motor units yielding fairly incomplete information about the behavior of individual motor units. We have begun a series of studies using high frequency sampling of the electromyogram to define the various motor units within the genioglossus muscle. These newer studies have revealed marked complexity in the behavior of the genioglossus muscle, with 6 distinct firing patterns being identifiable. A rise or fall in the genioglossal multiunit EMG is therefore difficult to interpret since these changes could be mediated by any of a number of individual motor unit firing changes. We have observed specific units that may be most critical for the maintenance of pharyngeal patency. Such units would thus we logical therapeutic targets which we can address with our neuroanatomy collaborators. We have also begun studies using single fiber EMGs and MacroEMGs which a view towards performing more quantitative assessments of various upper airway muscles. These newer EMG techniques will allow us to assess the mechanisms underlying the high level of activity seen in the EMG of sleep apnea patients as compared with controls, since there is currently an ongoing controversy as to whether this high activity represents high central drive to the muscle versus an effect of denervation. This K24 award would allow us to pursue interesting hypotheses that may ultimately lead to new treatments for sleep apnea, but will certainly yield insights into disease pathogenesis. This award will also allow the PI to dedicate more time to training young investigators in the field of sleep and respiratory physiology. The need for an investigator pipeline has been termed a crisis (Sleep. 2006 291260) RELEVANCE (See instructions) Obstructive sleep apnea is strongly implicated in motor vehicle accidents as well as high blood pressure and stroke. How easily an individual wakes up from sleep (arousal threshold) is something that may be important in why sleep apnea occurs. We propose studies that will examine the role of the arousal threshold with an ultimate goal of developing new treatments for sleep apnea to prevent its serious complications. (End of )
Keywords: ing; Address; Advocate; Affect; Animals; Arousal; awake; Award; base; Behavior; Behavioral; Breathing; Carbon Dioxide; Cardiovascular system; career development; Chemical Stimulation; Data; Deglutition; Denervation; density; Development; Dilator; Disease; Drops; Environmental air flow; falls; Fiber; Frequencies (time pattern); Goals; High Prevalence; Human; Hypercapnia; Hypertension; improved; Individual; insight; Instruction; interest; Iron; Lead; Lung; Maintenance; Mechanical Stimulation; Mechanics; Mediating; Mentors; Methods; Mid-Career Clinical Scientist Award (K24); Modeling; Motor; motor control; Muscle; Neuroanatomy; Neurocognitive; neuroregulation; new therapeutic target; novel strategies; Obstructive Sleep Apnea; Pathogenesis; Patients; Pattern; Phase; pressure; prevent; Recruitment Activity; reinnervation; relating to nervous system; REM Sleep; Research; Research Activity; Research Personnel; Research Project Grants; research study; respiratory; Respiratory physiology; response; Role; Sampling; Series; Sleep; Sleep Apnea Syndromes; sleep onset; Source; Stimulus; stroke; Techniques; Testing; therapeutic target; Time; Tongue; Training; Trigeminal Nuclei; vehicular accident; Wakefulness; Withdrawal; Work
Project start date: 2009-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-151
5K24HL093218-03 (2011): $173378