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DNA Methylation Profiling of Blood Monocytes in Patients With Obesity Hypoventilation Syndrome: Effect of Positive Airway Pressure Treatment.

ABSTRACT: OSA is a highly prevalent condition that is associated with a wide range of long-term morbidities including metabolic, cardiovascular, and cognitive alterations, possibly via activation of systemic inflammatory and oxidative stress pathways. Implementation of positive airway pressure (PAP) is the first-line treatment for OSA, as well as for obesity hypoventilation syndrome (OHS), its most severe phenotype. However, the molecular and cellular mechanisms underlying OHS-induced morbidities and their response to PAP treatment remain unclear, and could be mediated, in part, by OSA-induced epigenetic changes.Blood was collected before starting PAP treatment (PRE group), as well as 6 weeks after PAP treatment (POST group) in 15 adult patients with OHS. DNA methylation profiles were studied by methylated DNA immunoprecipitation coupled to microarrays (MeDIP-chip) in six representative patients and further verified in a cohort of 15 patients by MeDIP-quantitative PCR.We identified 1,847 regions showing significant differential DNA methylation (P < .001; model-based analysis of tiling arrays score, > 4) between the groups. Analysis of biochemical pathways and gene networks demonstrated that differentially methylated regions were associated with immune responses, and particularly with mechanisms governing gene regulation by peroxisome proliferation-activated receptors (PPARs). Single-locus quantitative PCR analysis revealed that DNA methylation was increased at the PPAR-responsive elements (PPAREs) of eight genes in the post-treatment samples (PRE/POST fold changes: ABCA1, 3.11; ABCG1, 1.72; CD36, 5.04; FABP4, 2.49; HMOX, 2.74; NOS2, 7.78; PEPCK, 9.27; and ADIPOQ, 1.73), suggesting that PAP treatment leads to an increase in DNA methylation at PPAREs, possibly affecting the binding of the PPAR-? complex and downstream gene expression.Our work provides initial evidence of epigenetic regulation particularly involving metabolic pathways in patients with OHS who are responsive to PAP treatment.

SUBMITTER: Cortese R

PROVIDER: S-EPMC6026248 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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DNA Methylation Profiling of Blood Monocytes in Patients With Obesity Hypoventilation Syndrome: Effect of Positive Airway Pressure Treatment.

Cortese Rene R Zhang Chunling C Bao Riyue R Andrade Jorge J Khalyfa Abdelnaby A Mokhlesi Babak B Gozal David D

Chest 20160226 1

<h4>Background</h4>OSA is a highly prevalent condition that is associated with a wide range of long-term morbidities including metabolic, cardiovascular, and cognitive alterations, possibly via activation of systemic inflammatory and oxidative stress pathways. Implementation of positive airway pressure (PAP) is the first-line treatment for OSA, as well as for obesity hypoventilation syndrome (OHS), its most severe phenotype. However, the molecular and cellular mechanisms underlying OHS-induced m ...[more]

PMID: 26923628

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Project description:Study objectivesTo assess the role of different levels of adherence and long-term effects of positive airway pressure (PAP) therapy on gas exchange, sleepiness, quality of life, depressive symptoms, and all-cause mortality in patients with obesity hypoventilation syndrome (OHS).MethodsA total of 252 patients with newly diagnosed OHS were followed up for a minimum of 2 years after PAP initiation. PAP adherence (h/night) was monitored. Arterial blood gas samples were taken with patients being alert for more than 4 hours after morning awakening. Subjective daytime sleepiness (Epworth Sleepiness Scale [ESS]), quality of life (Short Form 36 [SF-36]) and patient's depressive symptoms (Beck Depression Inventory [BDI]) were assessed before and at the end of the follow-up period, along with all-cause mortality.ResultsAt the end of the follow-up period (median duration [25th-75th percentile], 30 [24-52] months), PaO2 increased from baseline (72.7 ± 10.3 versus 63.2 ± 10.6, P < .001) and both PaCO2 and HCO3- decreased (43.0 [39.2-45.0] versus 50.0 [46.7-55.4] and 27.5 ± 3.2 versus 31.4 ± 4.2, respectively, P < .001). In addition, PAP therapy significantly improved ESS (7 [4-9] versus 14 [11-16], P < .001), BDI (8.8 ± 4.9 versus 15.5 ± 7.3, P < .001) and SF-36 (82 [78-87] versus 74 [67-79], P < .001) scores. Over the follow-up period 11 patients died. Patients who used PAP for > 6 h/night had significant improvements (P < .05) in blood gases and SF-36 scores than less adherent patients.ConclusionsIncreased hours of use and long-term therapy with PAP are effective in the treatment of patients with OHS. Clinicians should encourage adherence to PAP therapy in order to provide a significant improvement in clinical status and gas exchange in these patients.CommentaryA commenary on this article appears in this issue on page 1455.Clinical trial registrationTitle: PAP Therapy in Patients With Obesity Hypoventilation Syndrome, Registry: ClinicalTrials.gov, Identifier: NCT03449641, URL: https://clinicaltrials.gov/ct2/show/NCT03449641.

Project description:Study objectivesPositive airway pressure (PAP) treatment of obstructive sleep apnea reduces blood pressure (BP). Retrospective data suggest that African Americans (AA), a group at high-risk for hypertensive organ dysfunction, may have a greater BP response to PAP therapy than European Americans (EA). We examined the difference in 24-hour BP response to 3 months of PAP treatment between AA and EA.MethodsParticipants (n = 259, 161 AA and 98 EA) with apnea-hypopnea index ≥ 15 events/h from 2 prospective cohorts were included. t-Tests and multiple linear regression were used to examine BP outcomes in AA vs EA, adjusting for PAP adherence, socioeconomic status, and baseline characteristics.ResultsParticipants were middle aged (mean ± SD, 53.8 ± 9.3 years), 86% (227) men, apnea-hypopnea index 35.6 ± 19.2 events/h, and PAP adherence of 3.36 ± 2.24 h/day. The reductions in 24-hour systolic and diastolic BP (mm Hg) were not different in AA vs EA (systolic = -1.13 ± 12.1 vs -0.61 ± 12.8, P = .80 and diastolic = -0.74 ± 7.9 vs -0.80 ± 7.4, P = .96), and race was not a predictor of 24-hour systolic or diastolic BP reduction (P = .75 and 0.54). Socioeconomic status and PAP adherence demonstrated a significant interaction; low socioeconomic status was associated with an increase in 24-hour systolic BP (β = 19.3, P = .03) in the absence of PAP use but a greater reduction in 24-hour systolic BP with higher PAP adherence (β = -3.96, P = .03).ConclusionsTwenty-four hour BP response to PAP treatment is similar in AA and EA. Adherence to PAP treatment is more effective in improving 24-hour systolic BP in those with low SES.Clinical trial registrationRegistry: ClinicalTrials.gov; Name: Race and CPAP Effectiveness (RACE); URL: https://clinicaltrials.gov/ct2/show/NCT01960465; Identifier: NCT01960465 and Registry: ClinicalTrials.gov; Name: The Effects of Treating Obese and Lean Patients with Sleep Apnea (PISA); URL: https://clinicaltrials.gov/ct2/show/NCT01578031; Identifier: NCT01578031.CitationImayama I, Gupta A, Yen PS, et al. Socioeconomic status impacts blood pressure response to positive airway pressure treatment. J Clin Sleep Med. 2022;18(5):1287-1295.

Project description:BackgroundIncreased pleural pressure affects the mechanics of breathing of people with class III obesity (BMI > 40 kg/m2).Research questionWhat are the acute effects of CPAP titrated to match pleural pressure on cardiopulmonary function in spontaneously breathing patients with class III obesity?Study design and methodsWe enrolled six participants with BMI within normal range (control participants, group I) and 12 patients with class III obesity (group II) divided into subgroups: IIa, BMI of 40 to 50 kg/m2; and IIb, BMI of ≥ 50 kg/m2. The study was performed in two phases: in phase 1, participants were supine and breathing spontaneously at atmospheric pressure, and in phase 2, participants were supine and breathing with CPAP titrated to match their end-expiratory esophageal pressure in the absence of CPAP. Respiratory mechanics, esophageal pressure, and hemodynamic data were collected, and right heart function was evaluated by transthoracic echocardiography.ResultsThe levels of CPAP titrated to match pleural pressure in group I, subgroup IIa, and subgroup IIb were 6 ± 2 cmH2O, 12 ± 3 cmH2O, and 18 ± 4 cmH2O, respectively. In both subgroups IIa and IIb, CPAP titrated to match pleural pressure decreased minute ventilation (IIa, P = .03; IIb, P = .03), improved peripheral oxygen saturation (IIa, P = .04; IIb, P = .02), improved homogeneity of tidal volume distribution between ventral and dorsal lung regions (IIa, P = .22; IIb, P = .03), and decreased work of breathing (IIa, P < .001; IIb, P = .003) with a reduction in both the work spent to initiate inspiratory flow as well as tidal ventilation. In five hypertensive participants with obesity, BP decreased to normal range, without impairment of right heart function.InterpretationIn ambulatory patients with class III obesity, CPAP titrated to match pleural pressure decreased work of breathing and improved respiratory mechanics while maintaining hemodynamic stability, without impairing right heart function.Trial registryClinicalTrials.gov; No.: NCT02523352; URL: www.clinicaltrials.gov.

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DNA Methylation Profiling of Blood Monocytes in Patients With Obesity Hypoventilation Syndrome: Effect of Positive Airway Pressure Treatment.

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DNA Methylation Profiling of Blood Monocytes in Patients With Obesity Hypoventilation Syndrome: Effect of Positive Airway Pressure Treatment.

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