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Sleep apnea insular glutamate and GABA levels

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Sleep Apnea Takes a Toll on Brain Function

UCLA   http://www.biosciencetechnology.com/news/2016/02/sleep-apnea-takes-toll-brain-function

 

One in 15 adults has moderate to severe obstructive sleep apnea, a disorder in which a person’s breathing is frequently interrupted during sleep — as many as 30 times per hour.

People with sleep apnea also often report problems with thinking such as poor concentration, difficulty with memory and decision-making, depression, and stress.

According to new research from the UCLA School of Nursing,  published online in the Journal of Sleep Research,  people with sleep apnea show significant changes in the levels of two important brain chemicals, which could be a reason that many have symptoms that impact their day-to-day lives.

UCLA researchers looked at levels of these neurotransmitters — glutamate and gamma-aminobutyric acid, known as GABA — in a brain region called the insula, which integrates signals from higher brain regions to regulate emotion, thinking and physical functions such as blood pressure and perspiration. They found that people with sleep apnea had decreased levels of GABA and unusually high levels of glutamate.

GABA is a chemical messenger that acts as an inhibitor in the brain, which can slow things down and help to keep people calm — like a brake pedal. GABA affects mood and helps make endorphins.

Glutamate, by contrast, is like an accelerator; when glutamate levels are high, the brain is working in a state of stress, and consequently doesn’t function as effectively. High levels of glutamate can also be toxic to nerves and neurons.

“In previous studies, we’ve seen structural changes in the brain due to sleep apnea, but in this study we actually found substantial differences in these two chemicals that influence how the brain is working,” said Paul Macey, the lead researcher on the study and an associate professor at the UCLA School of Nursing.

Macey said the researchers were taken aback by the differences in the GABA and glutamate levels.

“It is rare to have this size of difference in biological measures,” Macey said. “We expected an increase in the glutamate, because it is a chemical that causes damage in high doses and we have already seen brain damage from sleep apnea. What we were surprised to see was the drop in GABA. That made us realize that there must be a reorganization of how the brain is working.”

Macey said the study’s results are, in a way, encouraging. “In contrast with damage, if something is working differently, we can potentially fix it.”

The link between sleep apnea and changes in the state of the brain is important news for clinicians, Macey said.

“What comes with sleep apnea are these changes in the brain, so in addition to prescribing continuous positive airway pressure, or CPAP — a machine used to help an individual sleep easier, which is the gold standard treatment for sleep disturbance — physicians now know to pay attention to helping their patients who have these other symptoms,” Macey said. “Stress, concentration, memory loss — these are the things people want fixed.”

In future studies, the researchers hope to determine whether treating the sleep apnea — using CPAP or other methods — returns patients’ brain chemicals back to normal levels. If not, they will turn to the question of what treatments could be more effective. They are also studying the impacts of mindfulness exercises to see if they can reduce glutamate levels by calming the brain.

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Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure

Writer: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Transvenous Phrenic Nerve Stimulation in Patients With Cheyne-Stokes Respiration and Congestive Heart Failure:A Safety and Proof-of-Concept Study

Xi-Long Zhang, MD; Ning Ding; Hong Wang; Ralph Augostini; Bing Yang; Di Xu; Weizhu Ju; Xiaofeng Hou; Xinli Li; Buqing Ni, PhD; Kejiang Cao; Isaac George; Jie Wang, MD, PhD; Shi-Jiang Zhang
Chest. 2012; 142(4):927-934. doi:10.1378/chest.11-1899
Text Size: A A A

Background:  Cheyne-Stokes respiration (CSR), which often occurs in patients with congestive heart failure (CHF), may be a predictor for poor outcome. Phrenic nerve stimulation (PNS) may interrupt CSR in patients with CHF. We report the clinical use of transvenous PNS in patients with CHF and CSR.

Methods:  Nineteen patients with CHF and CSR were enrolled. A single stimulation lead was placed at the junction between the superior vena cava and brachiocephalic vein or in the left-side pericardiophrenic vein. PNS stimulation was performed using Eupnea System device (RespiCardia Inc). Respiratory properties were assessed before and during PNS. PNS was assessed at a maximum of 10 mA.

Results:  Successful stimulation capture was achieved in 16 patients. Failure to capture occurred in three patients because of dislocation of leads. No adverse events were seen under maximum normal stimulation parameters for an overnight study. When PNS was applied following a series of central sleep apneic events, a trend toward stabilization of breathing and heart rate as well as improvement in oxygen saturation was seen. Compared with pre-PNS, during PNS there was a significant decrease in apnea-hypopnea index (33.8 ± 9.3 vs 8.1 ± 2.3, P = .00), an increase in mean and minimal oxygen saturation as measured by pulse oximetry (89.7% ± 1.6% vs 94.3% ± 0.9% and 80.3% ± 3.7% vs 88.5% ± 3.3%, respectively, all P = .00) and end-tidal CO2 (38.0 ± 4.3 mm Hg vs 40.3 ± 3.1 mm Hg, P = .02), but no significant difference in sleep efficiency (74.6% ± 4.1% vs 73.7% ± 5.4%, P = .36).

Conclusions:  The preliminary results showed that in a small group of patients with CHF and CSR, 1 night of unilateral transvenous PNS improved indices of CSR and was not associated with adverse events.

Trial registry:  ClinicalTrials.gov; No.: NCT00909259; URL: www.clinicaltrials.gov

http://journal.publications.chestnet.org/article.aspx?articleid=1215995

Transvenous phrenic nerve stimulation in patients with Cheyne-Stokes respiration and congestive heart failure: a safety and proof-of-concept study

Zhang Xi-Long; Ding N, Wang H, Augostini R, Yang B.
CHEST 2012; 142(4):927–934
Trial registry: ClinicalTrials.gov; No.: NCT00909259; URL: http://www.clinicaltrials.gov
http://dx.doi.org/10.1378/chest.11-1899

Introduction

Cheyne-Stokes respiration (CSR), a condition characterized by a cyclic pattern of waxing and waning ventilation interposed by central apneas or hypopneas, may affect up to 40% of patients with congestive heart failure (CHF).  Whether CSR is related to significantly increased morbidity and mortality 2 or has no impact on long-term survival in patients with CHF is controversial. Nevertheless, several investigators have reported that CSR might be an independent prognostic index of poor outcome in patients with CHF, so that Cheyne-Stokes respiration (CSR), which often occurs in patients with congestive heart failure (CHF), may be a predictor for poor outcome. CSR in patients with CHF is believed to be associated with a hypersensitivity to arterial CO 2 during sleep. The key pathophysiologic mechanism leading to all forms of periodic breathing is the oscillation of blood CO 2 level below and above the apneic threshold.  Clinically, these pathophysiologic changes may translate to sleep fragmentation, excessive daytime sleepiness, reduced exercise capacity, and, possibly, ventricular arrhythmias.
Current treatment options for CSR include medications, positive airway pressure devices such as adapt servo-ventilation, or oxygen therapy. Although all these therapies have shown benefi t in some patients, none has shown a consistent benefi t of suffi cient clinical magnitude to reduce mortality and morbidity. In the current study, we explored the initial feasibility, safety, and possible effects of unilateral, transvenous, synchronized PNS on CSR in 19 patients with CHF . This novel treatment resulted in a marked reduction of minute ventilation and possible improvement of CSR. The authors here suggest that phrenic nerve stimulation (PNS) may interrupt CSR in patients with CHF.

Study Population

 Nineteen patients with CHF and CSR were enrolled.  All study patients (N 5 19) had received a diagnosis of CSR and chronic CHF and were hospitalized in The First Affiliated Hospital of Nanjing Medical University (Nanjing, China). Of them, 12 with rheumatic cardiac valve disease were waiting forcardiac surgery, and seven (fi ve with dilated cardiomyopathy and two with hypertensive heart disease) were enrolled from the cardiology ward because of severe heart failure.
The inclusion criteria were aimed at identifying patients with symptoms or a diagnosed condition indicative of CSR who would tolerate the testing procedure. The patients continued on their standard medical regimen during participation, and in the case of an adverse event, medical treatment was at the discretion of the investigator. The inclusion criteria were as follows: (1) both patient and direct family member willingness to sign a Patient Ethics Committee-approved informed consent, (2) age > 18 years, (3) index CSR of > 15 times/h, (4) history of CHF with a left ventricle ejection fraction < 45%, and (5) ability to tolerate the study procedure and remain clinically stable for the duration of the study. Exclusion criteria were as follows: (1) baseline oxygen saturation <  90% on a stable FiO2 ; (2) evidence of phrenic nerve palsy; (3) temperature > 38.0°C; (4) inability to place stimulation lead (eg, coagulopathy, distorted anatomy, etc); (5) current enrollment in another clinical study that may confound the results of the present study; (6) no informed consent; (7) pregnancy or of childbearing potential without a negative pregnancy test within 10 days of the study procedure; (8) pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization device; (9) severe COPD; (10) a history of myocardial infarction within 6 months prior to the study; and (11) unstable angina.

Study Design

 This short-term, prospective, open-label, nonrandomized feasibility study consisted of a treatment-only cohort in which each patient served as his or her own control. After patients were screened and enrolled in the study, PNS leads were placed through an interventional procedure for observation of 1 night only. During the 1-night study, we examined whether PNS caused pain, arousal during sleep, arrhythmia, changes in BP, and changes in either normal breathing or sleep apnea. We also examined the impact of PNS on central, obstructive, and mixed sleep apnea. Alterations in sleep apnea and hypopnea events were compared before and during PNS. “Before stimulation” was defined as the number of sleep apnea and hypopnea events occurring during a segment of 10 min just before delivery of PNS and served as the control for the effects of PNS. The total number of the 10-min segments before PNS, the total number of sleep apnea and hypopnea events occurred during the sum of the 10-min time were calculated,  then averaged (total number of sleep apnea and hypopnea events/total hours of the 10-min segments from all patients) and presented as the apnea-hypopnea index (AHI) for statistical analysis. AHI during PNS were also calculated and compared with AHI prior to PNS.

Sleep Study and Monitored Parameters

 All participants underwent a nocturnal, in-laboratory polysomnography (Embla S4500 PSG Amplifi er; Natus Medical Inc) and were monitored for at least 7 h overnight. The standard polysomnography recorded the EEG, bilateral electrooculograms, submental  electromyogram, ECG, chest and abdominal movement using respiratory effort bands, body position, nasal airflow using a pressure sensor, and oxygen saturation as measured by pulse oximetry (Sp o 2 ).
EEG, sleep staging, and arousals were monitored and scored using 30 epochs according to the method of Rechtschaffen and Kales. Classification of apnea and hypopnea was described by standard methodologies. CSR was identified as a special kind of CSA behaving as a cyclic pattern of periods of hyperventilation with waxing and waning tidal volumes alternating with periods of central hypopnea/apnea .

Lead Placement and PNS

A single stimulation lead was placed at the junction between the superior vena cava and brachiocephalic vein or in the left-side pericardiophrenic vein. PNS stimulation was performed using Eupnea System device (RespiCardia Inc). Respiratory properties were assessed before and during PNS. PNS was assessed at a maximum of 10 mA.

Results

Successful stimulation capture was achieved in 16 patients. Failure to capture occurred in three patients because of dislocation of leads. No adverse events were seen under maximum normal stimulation parameters for an overnight study.  No new arrhythmias, muscle contractions, arterial BP variations, pain, or unpleasant sensations were observed once PNS was delivered during sleep for these patients. It was confirmed that the catheter could be secured adequately to obtain consistent predictable stimulation thresholds without arousal from sleep. During occurrence of CSR, intermittent PNS signals were first confirmed to be successfully captured in 16 patients. When PNS was applied following a series of central sleep apneic events, a trend toward stabilization of breathing and heart rate.  An improvement in oxygen saturation and elevation of end-tidal CO2 was observed as longer continuous stimulation was performed. The period of stable breathing lasted as long as 10 to 20 min in some patients after stimulation.  They found that when electric connection to the nerve was consistent, stimulation resulted in a reduced hyperventilation followed by the reduction or elimination of CSR.
Compared with pre-PNS, during PNS there was a significant decrease in apnea-hypopnea index (33.8 ± 9.3 vs 8.1 ± 2.3, P = .00), an increase in mean and minimal oxygen saturation as measured by pulse oximetry (89.7% ± 1.6% vs 94.3% ± 0.9% and 80.3% ± 3.7% vs 88.5% ± 3.3%, respectively, all P = .00) and end-tidal CO2 (38.0 ± 4.3 mm Hg vs 40.3 ± 3.1 mm Hg, P = .02), but no significant difference in sleep efficiency (74.6% ± 4.1% vs 73.7% ± 5.4%, P = .36).

Discussion

CSR is characterized by cyclical oscillations of respiration and apnea. The incidence of CSR ranges from 10% to 20% in patients with stable CHF and up to 40% to 50% of all patients with New York Heart Association functional class III?IV CHF.  Nocturnal breathing alterations in patients with CHF are believed to be due to hypersensitivity to CO 2 during sleep. Breathing is controlled by a negative feedback system in which an increase in Pa co 2 stimulates breathing, whereas a decrease in Pa co 2 inhibits breathing. Normally, Pa co 2 is maintained within a narrow range. Patients with CHF and CSA have a more brisk ventilatory response to CO 2 than those without CSA.
The preliminary results showed that in a small group of patients with CHF and CSR, 1 night of unilateral transvenous PNS improved indices of CSR and was not associated with adverse events.
The study was performed using temporary catheters or leads in the right-side brachiocephalic vein, SVC, or left-side pericardiophrenic vein to transvenously stimulate the hemidiaphragm through either the leftside or the right-side phrenic nerve. To consistently stimulate the phrenic nerve using acceptable and safe current levels ( < 10 mA), the stimulation electrode needs to be within 2 to 5 mm from the phrenic nerve.  This type of stimulation caused significantly improved respiratory parameters in patients with CHF and further support that oscillation of CO 2 level in the blood below and above the apneic threshold is a central mechanism leading to the CSR pattern of breathing. Stabilization of CO 2 levels through PNS produced a regular breathing pattern, improvement in oxygen saturation, and fewer apneic events.
Dr.  Isaac George: contributed to data evaluation and drafting of the manuscript.

Related articles

Other related articles published on this Open Access Online Scientific Journal include the following:

Implantable Synchronized Cardiac Assist Device Designed for Heart Remodeling: Abiomed’s Symphony

Aviva Lev-Ari, PhD, RN, 7/11/2012

https://pharmaceuticalintelligence.com/2012/07/11/implantable-synchronized-cardiac-assist-device-designed-for-heart-remodeling-abiomeds-symphony/

Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/5_04_2013/bernstein_lev-ari/Bioengineering_of_Vascular_and_Tissue_Models

Foreseen changes in Guideline of Treatment of Cardiogenic Shock with Intra-aortic Balloon counterPulsation (IABP)

Evidence for Overturning the Guidelines in Cardiogenic Shock

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

Aviva Lev-Ari, PhD, RN, 6/3/2013

Aviral Vatsa PhD MBBS, 1/4/2013

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Aviva Lev-Ari, PhD, RN, 10/19/2013

https://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Justin Pearlman MD ME PhD MA FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

Visualisation of Cheyne-Stokes respiration

Visualisation of Cheyne-Stokes respiration (Photo credit: Wikipedia)

Cheyne-Stokes respiration

Cheyne-Stokes respiration (Photo credit: Wikipedia)

Cheyne-Stokes respiration

Cheyne-Stokes respiration (Photo credit: Wikipedia)

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Sleep apnea and non-invasive positive pressure breathing

Curator: Larry H Bernstein, MD, FCAP

 

UPDATED on 10/24/2019

Researchers identify genetic variations linked to oxygen drops during sleep

“This study highlights the advantage of using family data in searching for rare variants, which is often missed in genome-wide association studies,” said James Kiley, Ph.D., director of the Division of Lung Diseases at NHLBI. “It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.”

Notably, 51 of the 57 genetic variants influence and regulate human lung fibroblast cells, a type of cell producing scar tissue in the lungs, according to study author Xiaofeng Zhu, Ph.D., professor at the Case Western Reserve University School of Medicine, Cleveland.

“This is important because Mendelian Randomization analysis, a statistical approach for testing causal relationship between an exposure and an outcome, shows a potential causal relationship between how the DLC1 gene modifies fibroblasts cells and the changes in oxygen levels during sleep,” he said.

https://www.nih.gov/news-events/news-releases/researchers-identify-genetic-variations-linked-oxygen-drops-during-sleep

 

Presentation of sleep apnea

Obstructive sleep apnea is caused by a blockage of the airway.  This may occur when the soft tissue in the rear of the throat collapses and closes during sleep. Sleep apnea causes SNORING, intermittent cessation of breathing during sleep, which the person having the sleep disturbance may be unaware of.  This results in reawaking and restless sleep, and concomitantly, daytime fatigue. Obstructive sleep apnea accounts for 85% of cases. According to some studies, one in every 15 Americans is affected by this condition, and only a small percentage of them get treated.

Treatment(s)

Weight loss and diabetic control might be sufficient for some who have a mild condition.  There are also breathing exercises, and the placement of an orthodontic specially fitted mouth guard that flattens the posterior mouth during sleep.  Those who have moderate to severe sleep apnea may require assisted beathing during sleep, or surgery.  The standard treatments are CPAP (continuous positive airway pressure ) or BiPAP (Bilevel positive airway pressure), the first being most commonly used.  However, the effectiveness is influenced by body positioning during sleep.  Many patients are unable to adjust to the CPAP mask, which has to fit snugly over the mouth and nose.

TransOral Robotic Surgery (TORS) for sleep apnea

A recently introduced surgical procedure that has gained wide use is transoral robotic surgery (TORS).
The use of da Vinci® robot-assisted surgery for treatment of obstructive sleep apnea is revolutionary due to the minimally invasive nature of the procedure.  The surgeon guides the robotic arms in through the patient’s mouth, and a high-definition [3D] camera allows the surgeon to perfectly visualize areas of the mouth and throat without any open incisions.  The surgery focuses on reducing the size of the base of the tongue. Patients are assessed during an in-office examination, which includes a review of recent sleep studies, and an evaluation with a scope to identify the level and nature  of obstruction.

The sleep apnea procedure (TORS) involves the actual surgery and a 1-2 day hospital stay after the surgery. Full recovery is expected to take about three weeks. A sleep study is then conducted about three months after surgery to ensure that the procedure was successful.

About CPAP

Continuous positive airway pressure or CPAP is used both in hospitals for newborn babies or those who suffer from respiratory failure, and in the home.  The device works by increasing pressure in the airway, preventing collapse while breathing in. The CPAP machine has tubing, a setting for the pressure, and a mask that covers the mouth and nose, delivering the air pressure into the nasal passages. The right air pressure for a patient is prescribed by the sleep physician after conducting a detailed overnight study of the patient’s breathing pattern. Such a prescribed air pressure is termed as ‘titrated pressure’. The CPAP machine, set at the prescribed air pressure , blows air at the titrated pressure, maintaining the air passage open for uninterrupted breathing during sleep.

CPAP Side Effects

Nasal Congestion: Use of CPAP machines may cause nasal congestion. Some patients may experience nasal irritation or a runny nose too. This is because of the fact that the nose humidifies the air that passes through it and the air from CPAP machine dries up the nose. The body reacts by producing more mucus in the nose, which leads to nasal congestion. In some patients, there will be no mucus production and this results in dry nose, which cause nasal irritation, burning or sneezing. CPAP machines with inbuilt humidifier may help you address this problem.  Other problems are ear pressure and difficulty from a deviated nasal septum.

CPAP Alternatives

Only 23% of individuals suffering from sleep apnea succeed in getting used to CPAP. A popular alternative to this machine are the intraoral dental appliances that consist of two U-shaped plates that are joined to form a hinge. These can be custom-made by a dentist or an orthodontist.   It adjusts the lower jaw and tongue of a user, so that the air passage does not collapse while sleeping. There are lingual tabs that hold the appliance in place.

CPAP Vs. BiPAP – Difference between CPAP and BiPAP

The Continuous Positive Airway Pressure (CPAP) machine gives a predetermined level of pressure. It releases a gust of compressed air through a hose which is connected to the nose mask. The continuous air pressure is what keeps the upper airway open. Thus, air pressure prevents obstructive sleep apnea, which occurs as a result of narrowing of the air passage due to the relaxation of upper respiratory tract muscles while the patient sleeps. It assists in increasing the flow of oxygen by keeping the airway open.

The Bilevel Positive Airway Pressure (BiPAP) is a patented, non-invasive ventilation machine. As the name suggest, it delivers two levels of pressure.  Inspiratory Positive Airway Pressure (IPAP) is a high level of pressure, applied when the patient inhales. Expiratory Positive Airway Pressure (EPAP), a low level of pressure exerted during exhalation.  BiPAP is used to treat central sleep apnea and severe obstructive sleep apnea, and It is prescribed for patients who suffer from respiratory and heart diseases.
Patients using the CPAP have to exert extra force against the air flow while exhaling, whereas with the BiPAP, the airway pressure is set at high and low levels, making it more user-friendly.

Relationship of sleep apnea syndrome to other complicating conditions

Macular edema

Sixteen of 22 obese diabetics of an apneic cohort had severe and six had moderate obstructive sleep apnea syndrome.  The cohort had an average of 44.6 + 21.9 apneic or hypopneic events per hour averaging 23.3 + 5.9 seconds, with oxygen saturation of 73.5 + 9.5% (normal 94%).  The patients had retinopathy manifesting multiple nerve-fiber layer infarcts, at least 3 in each eye, and more than 6 infarcts in most eyes, with microvascular leakage and macular edema.  This finding was rare among the cohort without sleep apnea.

Laparoscopic surgery has been associated with ventilator complications, contingent on cardiac and respiratory comorbidities, and body habitus., particularly morbidly obese patients receiving general anesthesia. The EZ PAP positive airway pressure system is an easily used, disposable device that delivers CPAP air flow from an oxygen flow meter, and has been predicted to improve oxygenation, reducxe CO2 retention, and lower the risk of respiratory complications postoperatively.  Patients in the EZ PAP group demonstrated improvement in ventilator effort in the first few hours postoperatively, but the measured benefit did not exceed 4 hours.  Interventions must be aimed at improvement for longer periods.

Sleep apnea is well documented to negatively affect neurocognitive and neuropsychiatric functioning, including memory, attention, mood, and anxiety.  It has been identified as a risk for developing Alzheimer’s disease, and TBI (traumatic brain injury) is a risk factor for developing dementia, expetially in those with the apolipoprotein epsilon 4 allele.  The majority of sleep apnea are male and TBI is common in veterans of combat,  the increased incidence of sleep disordered breathing in TBI patients (SDB in TBI in 50-70% of patients) is of interest to the Department of Veterans Affairs.  A recent review by O’Hara et al. found that sleep apnea interacted with APOE ε4 and carried increased risk for poor cognitive performance.  Moreover, SNPs within the APOE gene (rs157580, rs405509, rs769455, and rs7412) all showed associations with OSA in children, with age and BMI as covariates.  This suggests that the interaction between TBI, OSA, and APOE genotype is quite complex.  Studies indicate that CPAP/BiPAP can be effective in reducing the sleep apnea and the cognitive sequelae.  The question is raised as  to whether the treatment of OSA might only target APOE ε4 carriers, but it is important to recognize that chronic pulmonary disease that increases hypoxia would factor in.

Treatment of Obstructive Sleep Apnea Reduces the Risk of Atrial Fibrillation Recurrence After Catheter Ablation

Objectives The aim of this study was to examine the effect of continuous positive airway pressure (CPAP) therapy on atrial fibrillation (AF) recurrence in patients with obstructive sleep apnea (OSA) undergoing pulmonary vein isolation (PVI).
Background OSA is a predictor of AF recurrence following PVI, but the impact of CPAP therapy on PVI outcome in patients with OSA is unknown.
Methods Among 426 patients who underwent PVI between 2007 and 2010, 62 patients had a polysomnography-confirmed diagnosis of OSA. While 32 patients were “CPAP users” the remaining 30 patients were “CPAP nonusers.” The recurrence of any atrial tachyarrhythmia, use of antiarrhythmic drugs, and need for repeat ablations were compared between the groups during a follow-up period of 12 months. Additionally, the outcome of patients with OSA was compared to a group of patients from the same PVI cohort without OSA.
Results CPAP therapy resulted in higher AF-free survival rate (71.9% vs. 36.7%; p = 0.01) and AF-free survival off antiarrhythmic drugs or repeat ablation following PVI (65.6% vs. 33.3%; p = 0.02). AF recurrence rate of CPAP-treated patients was similar to a group of patients without OSA (HR: 0.7, p = 0.46). AF recurrence following PVI in CPAP nonuser patients was significantly higher (HR: 2.4, p < 0.02) and similar to that of OSA patients managed medically without ablation (HR: 2.1, p = 0.68).
Conclusions CPAP is an important therapy in OSA patients undergoing PVI that improves arrhythmia free survival.
Comment: . The current study extends similar benefits to those undergoing catheter ablation to those undergoing elective cardioversion of atrial fibrillation with a better long term success when OSA patients are treated with CPAP.
J Am Coll Cardiol. 2013;62(4):300-305.   http://dx.doi.org/10.1016/j.jacc.2013.03.052  

References:

A putative relationship between OSA and diabetic macular edema associated with optic nerve fiber layer infarcts.
Unver YB, Yavuz GSA, Stafford CA, Sinclair SH.
The  Open Sleep Journal 2009;2:11-19.       1874-6209/09
http://www.benthamscience.com/open/toslpj/articles/V002/11TOSLPJ.pdf

EZ-PAP in the postoperative period: a pilot study.
Talley HC, Twiss K, Wilkinson S, et al.
J Anesth Clin Res 2012; 3:8
http://dx.doi.org/10.4172/2155-6148.1000236

Continuous positive airway pressure devices for the treatment of obstructive sleep apnea-hypopnea syndrome: a systematic review and economic analysis.
McDaid C,  Griffin S, Weatherly H, Duree K, et al.
High Technology Assessment 2009; 13(4):1-136
http://dx.doi.org/10.3310/hta13040

Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: Mechanism for cognitive dysfunction and development of dementia.
O’Hara R, Luzon A, Hubbard J, Zeitzer JM.
J Rehab Res Develop  2009; 46(6):837-850.
http://dx.doi.org/10.1682/JRRD.2008.10.0140

English: The Cycle of Obstructive Sleep Apnea ...

English: The Cycle of Obstructive Sleep Apnea – OSA (Photo credit: Wikipedia)

English: This is my own machine of which I too...

English: This is my own machine of which I took the picture. (Photo credit: Wikipedia)

Young Innovator Develops bCPAP to Save Babies ...

Young Innovator Develops bCPAP to Save Babies Lives (Photo credit: USAID_IMAGES)

English: Medical report showing the duration a...

English: Medical report showing the duration and frequency of sleep apnea of a test subject. Duration and frequencies are sorted by the sleeper’s position in bed. Français : Analyse de la durée et du nombre d’apnées en fonction de la position du dormeur. (Photo credit: Wikipedia)

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How Might Sleep Apnea Lead to Serious Health Concerns like Cardiac and Cancer?

Author: Larry H Bernstein, MD, FCAP

 

UPDATED on 7/23/2019

Israel-led research team develops AI-based model to detect sleep apnea | The Times of Israel

https://www.timesofisrael.com/israel-led-research-team-develops-ai-based-model-to-detect-sleep-apnea/?utm_source=dlvr.it

 

What is the link between sleep apnea and cardiovascular disease and is the treatment of obstructive sleep apnea (OSA) by continuous positive airway pressure in patients (CPAP) with heart failure to improve left ventricular systolic function sufficient?  There are statistics incicating the benefit of CPAP and improvement of LVSF in those patients on CPAP with CHF.  But that observation does not get at why the patients benefit, or whether the OSA is sufficient.  Don’t expect a randomized clinical trial of any design to be brought to bear on the subject, considering the ethical issues involved.  We’ll return to that in a moment.
In a recent study researchers in Spain followed thousands of patients at sleep clinics and found that those with the most severe forms of sleep apnea had a 65 percent greater risk of developing cancer of any kind. The second study, of about 1,500 government workers in Wisconsin, showed that those with the most disordered sleep had five times the rate of dying from cancer as people without the sleep disorder (apnea not specified). Both research teams only looked at cancer diagnoses and outcomes in general.  If I lump the two studies, assuming that all patients with the most disordered sleep had OSA and were on CPAP, what does this tell us?  The heart and lung function together as a cardiopulmonary oxygenation unit!  A problem disrupting oxygenation, such as autonomically controlled sleep disruption or, oronasal obstruction (ASSOCIATED WITH SNORING), would be expected to have an effect on alertness during the day, predisposition to CHF from strain on the CP circulation as well as ventilatory impairment and peripheral oxygenation.  It appears that an association with ANY cancer, unspecified, is a long reach.
In both studies the researchers ruled out the possibility that the usual risk factors for cancer, like
  1. age
  2. smoking
  3. alcohol use
  4. physical activity
  5. weight
The association between cancer and disordered breathing at night remained
  • even after they adjusted for confounding variables.
This led to the conclusion that cancer might be linked to (intermittent) lack of oxygen supply interrupting aerobic cell activity over long periods of time.  The conclusion is drawn that from two associations
  • the research on positive outcome from CPAP in OSA and
  • a possible link between breathing and cardiac and cancer clearly
demonstrates the importance of regular breathing exercises (other wise known as ‘Pranayama’ in India) as part of our every day life.
This answers the first observation I posed. That is, the use of CPAP, while enormously important, is not sufficient.  Regular breathing exercises would seem to be helpful, although not a standard part of current treatment. This would be especially important if the movement of the abdominal muscles and diaphragm were synchronized with the expansion of the nthorax for maximum air flow.  This observation is familiar from working with a certified exercise physiologist.   The other part of this is an optimum time for walking and carrying out basic muscle and flexibility exercises several times a week, which has been shown repeatedly by studies on health benefits.
It is not my place to raise some questions about the way the studies were carried out.  The patients who have sleep apnea would be expected to have an increased body mass index (BMI), and while not sarcopenic, more likely to have excess body fat, abdominal distribution in males, and hip distribution in females, amd more importantly, unseen fat in the abdominal peritoneum.  This is related to type 2 diabetes with a metabolic syndrome, a separate indicator of CVD risk.   The metabolic syndrome involves TNF-alpha (once also known as cachexin), IL-1, IL-6, C-reactive protein, and in the case of fat signaling, adipokines, as well as insulin resistance and, as a result, some counter-regulatory secretion of glucocorticosteroids.  This metabolic picture would result in the following:
  1. impaired glucose utilization
  2. some excess and uncompensated gluconeogenesis
  3. the impaired lactate reentry at the end of glycolysis
  4. an effect on allosteric PFK
Features 1-4 look like what Warburg called a Pasteur Effect, not at the clellular level, but in the whole individual.   While obesity and type 2 diabetes are occuring in the young and adolescent population, the consequences might not be seen until years later.  The consequences could be in a middle aged person falling asleep at a meeting, or a series of automabile accidents related to falling asleep at the wheel.
At a time that clinical laboratory measurements are so accurate, and
  • the associations between type 2 diabetes,
  • measurement of wt/ht^2,
  • arm strength,
  • skin fold thickness,

are common measures of fitness, they don’t appear to have any place in these studies. If that is the case, then how is it possible to make sense of a relationship between SEVERITY of sleep disturbance and health outcome.

English: The Cycle of Obstructive Sleep Apnea ...

English: The Cycle of Obstructive Sleep Apnea – OSA (Photo credit: Wikipedia)

English: The graph shows the correlation betwe...

English: The graph shows the correlation between body mass index (BMI) and percent body fat (%BF) for men in NCHS’ NHANES III 1994 data. The body fat percent shown uses the method from Romero-Corral et al. to convert NHANES BIA to %BF (June 2008). “Accuracy of body mass index in diagnosing obesity in the adult general population”. International Journal of Obesity 32 (6) : 959–956. DOI:10.1038/ijo.2008.11. PMID 18283284. (Photo credit: Wikipedia)

English: Body mass index, BMI, body size, body...

English: Body mass index, BMI, body size, body weight, mortality Italiano: indice di massa corporea, IMC, altezza corporea, peso corporeo, mortalità (Photo credit: Wikipedia)

Italiano: biometria, epidemiologia, rischio, p...

Italiano: biometria, epidemiologia, rischio, peso corporeo umano, mortalità, indice di massa corporea, IMC, body mass index, BMI, prospective studies collaboration (Photo credit: Wikipedia)

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English: The illustration shows the major sign...

English: The illustration shows the major signs and symptoms of heart failure. (Photo credit: Wikipedia)

Link between sleep apnea and cardiovascular disease is an established fact and one recent study further supported that treatment of obstructive sleep apnea by continuous positive airway pressure in patients (CPAP) with heart failure would improve left ventricular systolic function.

In a recent study researchers in Spain followed thousands of patients at sleep clinics and found that those with the most severe forms of sleep apnea had a 65 percent greater risk of developing cancer of any kind. The second study, of about 1,500 government workers in Wisconsin, showed that those with the most breathing abnormalities at night had five times the rate of dying from cancer as people without the sleep disorder. Both research teams only looked at cancer diagnosesand outcomes in general, without focusing on any specific type of cancer.

CPAP user Svenska: CPAP-brukare

CPAP user Svenska: CPAP-brukare (Photo credit: Wikipedia)

In both studies the researchers ruled out the possibility that the usual risk factors for cancer, like age, smoking, alcohol use, physical activity and weight, could have played a role. The association between cancer and disordered breathing at night remained even after they adjusted these and other variables.

They are of the opinion that cancer linked to possible lack of oxygen or anaerobic cell activity over long periods of time, therefore, it’s possible poor breathing fails to oxygenate the cells sufficiently.

Instructor de Kundalini yoga practicando Pranayama

Instructor de Kundalini yoga practicando Pranayama (Photo credit: Wikipedia)

Thus I personlly believe that the research on positive outcome on possible link between breathing and cardiac and cancer clearly demonstrates the importance of regular breathing exercises (other wise known as ‘Pranayama’ in India) as part of our every day life.

http://www.nejm.org/doi/full/10.1056/NEJMoa022479#t=articleTop

http://well.blogs.nytimes.com/2012/05/20/sleep-apnea-tied-to-increased-cancer-risk/

http://www.medicalnewstoday.com/articles/245649.php

http://www.sciencenews.org/view/generic/id/340838/title/Severe_sleep_apnea_tied_to_cancer_risk

Curator: Dr. V.S. Karra, Ph.D.

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