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Publication Record


Relation of Obstructive Sleep Apnea and a Common Variant at Chromosome 4q25 to Atrial Fibrillation.
Patel NJ, Wells QS, Huang S, Upender RP, Darbar D, Monahan K
(2017) Am J Cardiol 119: 1387-1391
MeSH Terms: Aged, Aged, 80 and over, Atrial Fibrillation, Case-Control Studies, Chromosomes, Human, Pair 4, Electrocardiography, Female, Genetic Predisposition to Disease, Genotype, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Polysomnography, Risk Factors, Severity of Illness Index, Sleep Apnea, Obstructive
Show Abstract · Added April 6, 2017
Obstructive sleep apnea (OSA) and single nucleotide polymorphisms (SNPs) at the 4q25 locus are associated with increased risk of atrial fibrillation (AF). Whether these associations are independent of traditional risk factors for AF remains unknown. Using billing code queries and manual chart review, we assembled a cohort of adults that underwent overnight polysomnography and at least 1 12-lead electrocardiogram. Case status was defined by electrocardiographic data in support of AF or documentation of AF by a staff cardiologist. Controls were defined by a lack of primary evidence of AF and absence of a diagnosis of AF in the medical record. OSA severity was categorized based on Apnea-Hypopnea Index. Genotyping for a key 4q25 SNP (rs2200733) was performed using the Sequenom platform. Logistic regression was used to test for associations of AF with OSA category and 4q25 SNP genotype while adjusting for age, gender, body mass index, ancestry, hypertension status, and heart failure status. The cohort consisted of 674 subjects (62 ± 13 years; 44% women), including 132 patients with AF. After adjustment for established risk factors, the association between AF and OSA severity was borderline significant (odds ratio 1.2, 95% CI 1.0 to 1.5). The association between AF and 4q25 SNP status remained significant in a fully adjusted model that included OSA severity (odds ratio 1.5, 95% CI 1.3 to 5.7). In conclusion, OSA severity and the chromosome 4q25 SNP genotype were associated with AF status independent of clinical risk factors. Knowledge of AF-related SNPs may enhance AF risk stratification for those undergoing polysomnography.
Copyright © 2017 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Heart rate variability during sleep in children with autism spectrum disorder.
Harder R, Malow BA, Goodpaster RL, Iqbal F, Halbower A, Goldman SE, Fawkes DB, Wang L, Shi Y, Baudenbacher F, Diedrich A
(2016) Clin Auton Res 26: 423-432
MeSH Terms: Aging, Autism Spectrum Disorder, Autonomic Nervous System, Child, Child, Preschool, Female, Heart Rate, Humans, Male, Polysomnography, Sleep, Sleep Stages, Sleep, REM
Show Abstract · Added October 14, 2016
PURPOSE - Autonomic dysfunction has been reported in autism spectrum disorders (ASD). Less is known about autonomic function during sleep in ASD. The objective of this study is to provide insight into the autonomic cardiovascular control during different sleep stages in ASD. We hypothesized that patients with ASD have lower vagal and higher sympathetic modulation with elevated heart rate, as compared to typical developing children (TD).
METHODS - We studied 21 children with ASD and 23 TD children during overnight polysomnography. Heart rate and spectral parameters were calculated for each vigilance stage during sleep. Data from the first four sleep cycles were used to avoid possible effects of different individual sleep lengths and sleep cycle structures. Linear regression models were applied to study the effects of age and diagnosis (ASD and TD).
RESULTS - In both groups, HR decreased during non-REM sleep and increased during REM sleep. However, HR was significantly higher in stages N2, N3 and REM sleep in the ASD group. Children with ASD showed less high frequency (HF) modulation during N3 and REM sleep. LF/HF ratio was higher during REM. Heart rate decreases with age at the same level in ASD and in TD. We found an age effect in LF in REM different in ASD and TD.
CONCLUSION - Our findings suggest possible deficits in vagal influence to the heart during sleep, especially during REM sleep. Children with ASD may have higher sympathetic dominance during sleep but rather due to decreased vagal influence.
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13 MeSH Terms
State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 - Relation to antipsychotic-like drug effects.
Gould RW, Nedelcovych MT, Gong X, Tsai E, Bubser M, Bridges TM, Wood MR, Duggan ME, Brandon NJ, Dunlop J, Wood MW, Ivarsson M, Noetzel MJ, Daniels JS, Niswender CM, Lindsley CW, Conn PJ, Jones CK
(2016) Neuropharmacology 102: 244-53
MeSH Terms: Allosteric Regulation, Animals, Arousal, Electroencephalography, Male, Polysomnography, Pyridazines, Rats, Receptor, Muscarinic M4, Sleep, Thiophenes
Show Abstract · Added February 18, 2016
Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M1/M4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a.
Landreth H, Malow BA, Shoemaker AH
(2015) Horm Res Paediatr 84: 1-5
MeSH Terms: Adolescent, Child, Female, Humans, Male, Obesity, Polysomnography, Prevalence, Pseudohypoparathyroidism, Risk Factors, Sleep Apnea Syndromes
Show Abstract · Added April 26, 2016
BACKGROUND/AIMS - Pseudohypoparathyroidism type 1a (PHP1a) is a rare genetic disorder. This study aimed to determine the prevalence of sleep apnea in children with PHP1a.
METHODS - Nineteen patients with PHP1a between the age of 2 and 21 years were enrolled prospectively using online advertisements. Parents completed a medical history and surveys to assess sleep behavior. Polysomnography records were obtained when available. In addition, 18 subjects were identified in a retrospective chart review of de-identified medical records with 2.3 million patient charts.
RESULTS - Parents reported sleep disturbance (94%) and daytime somnolence (81%) in their children with PHP1a. In the retrospective chart review, 39% had a history of sleep apnea versus 8.8% of a similarly obese control group. In the combined analysis (n = 31), 52% had a history of snoring and 45% had a diagnosis of sleep apnea. Patients were obese with a mean BMI z-score of 2.20 ± 0.59. Patients with sleep apnea were significantly younger than those without a diagnosis (8.1 ± 5.4 vs. 12.8 ± 5.0 years, p = 0.02).
CONCLUSIONS - Children with PHP1a have a 4.4-fold greater relative risk of sleep apnea than similarly obese children. Screening for sleep apnea in this population may be warranted to prevent adverse health outcomes.
© 2015 S. Karger AG, Basel.
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11 MeSH Terms
Obstructive sleep apnea and progression of coronary artery calcium: the multi-ethnic study of atherosclerosis study.
Kwon Y, Duprez DA, Jacobs DR, Nagayoshi M, McClelland RL, Shahar E, Budoff M, Redline S, Shea S, Carr JJ, Lutsey PL
(2014) J Am Heart Assoc 3: e001241
MeSH Terms: Age Factors, Aged, Aged, 80 and over, Calcinosis, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Confidence Intervals, Coronary Angiography, Coronary Artery Disease, Disease Progression, Female, Follow-Up Studies, Humans, Male, Middle Aged, Polysomnography, Predictive Value of Tests, Prospective Studies, Risk Assessment, Sex Factors, Sleep Apnea, Obstructive, Time Factors
Show Abstract · Added October 10, 2014
BACKGROUND - Obstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self-reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association.
METHODS AND RESULTS - In the Multi-Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002-2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010-2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA ("normal"). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow-up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group.
CONCLUSIONS - OSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.
© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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23 MeSH Terms
Severity of obstructive sleep apnea influences the effect of genotype on response to anti-arrhythmic drug therapy for atrial fibrillation.
Goyal SK, Wang L, Upender R, Darbar D, Monahan K
(2014) J Clin Sleep Med 10: 503-7
MeSH Terms: Anti-Arrhythmia Agents, Atrial Fibrillation, Female, Genetic Predisposition to Disease, Genotype, Genotyping Techniques, Humans, Male, Middle Aged, Pilot Projects, Polysomnography, Severity of Illness Index, Sleep Apnea, Obstructive, Treatment Outcome
Show Abstract · Added January 20, 2015
STUDY OBJECTIVES - To examine the impact of genotype on the relationship between obstructive sleep apnea (OSA) and anti-arrhythmic drug (AAD) efficacy in atrial fibrillation (AF).
DESIGN - Registry based.
SETTING - Clinic-based.
PARTICIPANTS - Eighty-four individuals from Vanderbilt AF registry who had polysomnography, genotyping, and serial comprehensive evaluations of AF status.
MEASUREMENTS AND RESULTS - Response to AADs was defined as a decrease in AF burden score by ≥ 75% or the combination of sinus rhythm on follow-up EKGs, stable AAD therapy for at least 6 months, objective AF burden below an established threshold, and the absence of non-pharmacologic therapies. Participants were genotyped for common AF susceptibility alleles at chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), and common SNPs in the β1-adrenergic receptor (ARDB1). Wild-type status for rs10033464 at 4q25 was associated with increased success of AAD therapy in patients with no or mild OSA (odds ratio: 10.0, 95% confidence interval: 1.03 to 97.5; p < 0.05), but did not influence response to AAD therapy in those with moderate-severe OSA. A similar trend was observed for rs1801252 on ARDB1.
CONCLUSION - In this hypothesis-generating pilot study of predominantly Caucasian men, the effect on AF response to AAD therapy of rs10033464 at 4q25 varied based on OSA status. The impact of genotype on AAD efficacy may be greatest in mild OSA and attenuated in more severe disease.
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14 MeSH Terms
Beyond adenotonsillectomy: outcomes of sleep endoscopy-directed treatments in pediatric obstructive sleep apnea.
Wootten CT, Chinnadurai S, Goudy SL
(2014) Int J Pediatr Otorhinolaryngol 78: 1158-62
MeSH Terms: Adenoidectomy, Adolescent, Anesthetics, Intravenous, Child, Child, Preschool, Down Syndrome, Endoscopy, Female, Glossectomy, Humans, Male, Oral Surgical Procedures, Palate, Soft, Polysomnography, Propofol, Recurrence, Sleep Apnea, Obstructive, Tonsillectomy, Turbinates, Uvula
Show Abstract · Added May 30, 2014
OBJECTIVES - In this study we determine the subjective and objective outcomes of pediatric patients with refractory OSA undergoing drug-induced sleep endoscopy (DISE)-directed surgical treatment.
METHODS - 31 consecutive children with OSA following TA underwent DISE. 26 completed DISE-directed operative management of the level(s) of ongoing upper airway obstruction. Pre- and postoperative OSA were assessed through a detailed history (of nighttime symptoms (NS) and daytime symptoms (DS)), physical examination, and polysomnography.
RESULTS - Age ranged 5-18 years (mean 9.7 ± 3.4). Fourteen of 26 had trisomy 21 (51%). Operations were performed in the following frequencies: lingual tonsillectomy (LT) (22), midline posterior glossectomy (MPG) (16), revision adenoidectomy (11), inferior turbinate submucosal resection (7), uvulopalatoplasty (2), and supraglottoplasty (2). Overall, 92% reported subjective improvement. NS improved from 5.8 ± 2.9 preoperatively to 2.1 ± 2.5 postoperatively (p<0.05), while DS improved from 2.1 ± 1.3 preoperatively to 0.6 ± 1.1 postoperatively (p<0.05). Seventeen patients completed preoperative polysomnography, while only 11 of them also completed postoperative polysomnography. Mean OAHI fell from 7.0 (±5.8) events/hr to 3.6 (±1.8) events/hr (t-test, p=0.09).
CONCLUSIONS - Individualized, multilevel, DISE-directed operative therapy was associated with substantial improvement in subjective measures of sleep.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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20 MeSH Terms
The authors reply.
Watson PL, Malow BA, Ely EW
(2014) Crit Care Med 42: e313-4
MeSH Terms: Electroencephalography, Female, Humans, Intensive Care Units, Male, Polysomnography, Respiration, Artificial, Sleep Stages
Added March 20, 2014
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8 MeSH Terms
Circadian variability of fibrinolytic markers and endothelial function in patients with obstructive sleep apnea.
Bagai K, Muldowney JA, Song Y, Wang L, Bagai J, Artibee KJ, Vaughan DE, Malow BA
(2014) Sleep 37: 359-67
MeSH Terms: Biomarkers, Body Mass Index, Cardiovascular Diseases, Case-Control Studies, Circadian Rhythm, Cross-Sectional Studies, Endothelial Cells, Female, Humans, Male, Middle Aged, Plasminogen Activator Inhibitor 1, Polysomnography, Sleep, Sleep Apnea, Obstructive, Tissue Plasminogen Activator
Show Abstract · Added March 10, 2014
STUDY OBJECTIVES - Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls.
SETTING - Cross-sectional cohort study.
PATIENTS OR PARTICIPANTS - Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA.
INTERVENTIONS - Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis.
MEASUREMENTS AND RESULTS - The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups.
CONCLUSION - The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.
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16 MeSH Terms
Atypical sleep in ventilated patients: empirical electroencephalography findings and the path toward revised ICU sleep scoring criteria.
Watson PL, Pandharipande P, Gehlbach BK, Thompson JL, Shintani AK, Dittus BS, Bernard GR, Malow BA, Ely EW
(2013) Crit Care Med 41: 1958-67
MeSH Terms: Aged, Electroencephalography, Female, Humans, Intensive Care Units, Male, Middle Aged, Monitoring, Physiologic, Polysomnography, Prospective Studies, Respiration, Artificial, Sampling Studies, Sleep Stages, Sleep, REM, Wakefulness
Show Abstract · Added March 20, 2014
OBJECTIVES - Standard sleep scoring criteria may be unreliable when applied to critically ill patients. We sought to quantify typical and atypical polysomnographic findings in critically ill patients and to begin development and reliability testing of methodology to characterize the atypical polysomnographic tracings that confound standard sleep scoring criteria.
DESIGN - Prospective convenience sample.
SETTING - Two academic, tertiary care medical centers.
PATIENTS - Thirty-seven critically ill, mechanically ventilated, medical ICU patients.
MEASUREMENTS AND MAIN RESULTS - Mechanically ventilated subjects were monitored by continuous polysomnography. After noting frequent atypical polysomnographic findings (i.e., lack of stage N2 markers, the presence of polymorphic delta, burst suppression, or isoelectric electroencephalography), attempts to use standard sleep scoring criteria alone were abandoned. Atypical polysomnographic findings were characterized and used to develop a modified scoring system. Polysomnographic data were scored manually via this revised scoring scheme. Of 37 medical ICU patients enrolled, 36 experienced atypical sleep, which accounted for 85% of all recorded data, with 5.1% normal sleep and 9.4% wake. Coupling observed patient arousal levels with polysomnographic characteristics revealed that standard polysomnographic staging criteria did not reliably determine the presence or absence of sleep. Rapid eye movement occurred in only five patients (14%). The revised scoring system incorporating frequently seen atypical characteristics yielded very high interrater reliability (weighted κ = 0.80; bootstrapped 95% CI, [0.48, 0.89]).
CONCLUSIONS - Analysis of polysomnographic data revealed profound deficiencies in standard scoring criteria due to a predominance of atypical polysomnographic findings in ventilated patients. The revised scoring scheme proved reliable in sleep staging and may serve as a building block in future work.
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15 MeSH Terms