Influence of Sleep Apnea on Risk of Atrial Fibrillation

Sleep-disordered breathing (SDB) is common in patients with cardiovascular disease and its attendant hypoxemia and autonomic dysfunction create a milieu that is likely to enhance AF propensity. Thus, SDB may represent a novel target for AF prevention and treatment strategies. Although our prior cross-sectional work has shown a 2-4 fold higher odds of AF related to SDB, these and other reports have not included cardiac structural data or autonomic/biochemical measures, and have addressed only arrhythmic events occurring during an overnight sleep study. In this proposal, we will examine paroxysmal AF (PAF), an early stage risk factor for persistent AF, and relevant to this proposal because it occurs prior to extensive cardiac electrical remodeling/fibrosis.

OUTLINE OF STUDY VISITS Baseline Visit (SA 1 and 2). After informed consent, eligible participants will be scheduled to arrive for an overnight visit in the CRU. During the evening, participants will undergo questionnaire administration, blood pressure measurements, and anthropometry. They will be provided dinner and undergo polysomnography (PSG). In the morning, participants will undergo fasting venipuncture, overnight urine collection, ECHO, 6 minute walk test, vascular measures and blood pressure measurements. For those with PAF (cases), hook-up for continuous ECG monitoring will be performed along with education regarding how to handle the device and bathing instructions, etc. All measurements in the DCRU/CRU will be performed blinded to PAF status. The only unblinded staff will be a dedicated research assistant who will perform the ECG monitoring hook-up. Blinded staff will collect and process data and perform data entry. After the baseline visit, participants with PAF (n=150) will undergo hook-up of the ECG monitor and an activity monitor at the baseline visit to wear for a 7-21 day period.

Follow-Up Visit (SA3). Those with SDB (AHI>=15) without evidence of central apnea (central apnea index>5) or Cheyne Stokes Respirations via baseline visit PSG and who have PAF will undergo the following. A 5-7 day home-based auto-titration (APAP, Respironics Autopap System One with humidifier) to identify the optimal positive airway pressure (PAP) setting will be performed (with settings 4-20cm H2O). At the end of the 5-7 day titration, the goal will be to identify the pressure that results in an AHI<5 events/hour (optimally). The research assistant will re-set the device to deliver this optimal fixed pressure identified by the PI through the secure wireless web-site. An overnight DCRUCRU visit will be scheduled after 3 months of wearing CPAP during which the same measures performed at the baseline visit will be collected.

STUDY PROCEDURES 2-DIMENSIONAL DOPPLER ECHOCARDIOGRAPHY. Parasternal, apical and subcostal 2-D views and apical 3D views will be obtained with transducer orientation and gain settings adjusted to optimally define endocardial surface of each cardiac chamber.

POLYSOMNOGRAPHY (PSG). Procedure for PSG: Research PSG will be performed using the Compumedics E-series system (Abbottsford, AU) which will include 3 cortical encephalograms, bilateral electro-oculograms, a bipolar submental electromyogram, thoracic and abdominal respiratory inductance plethysmography, airflow (by nasal-oral thermocouple and nasal cannula pressure recording), oximetry (using highly sensitive finger pulse oximeter, sampling frequency 25Hz), electrocardiogram (ECG) at 250Hz (used to derive HRV measures of autonomic function); body position (mercury switch sensor), bilateral leg movements. EEGs are recorded at 125Hz. 3) 7-21 Day CONTINUOUS ECG MONITORING.

Procedure: A 3-lead (2 channel), wireless, lightweight ECG monitoring device will be used to collect the ECG data over a 7-21 day period in those with PAF after the baseline and follow-up CRU visits.

ACTIVITY MONITORING. Procedure: An accelerometer (GT3X+, Actigraph Co., Ft Walton Bch, Fl) will be used for 7-21 days, coincident with the time of continuous ECG monitoring.

FASTING VENIPUNCTURE (52cc). Procedure: Phlebotomy will be performed the morning of the baseline and follow-up visits using standard techniques by trained research staff following written procedures. 6) DNA collection. Blood will be collected to extract RNA, which will be stored to test future hypotheses regarding genetic determinants of treatment response.

OVERNIGHT URINE. Procedure: Overnight urine collection will be performed. ANTHROPOMETRY. Height (inches, cm), neck circumference (cm), waist circumference (cm), hip circumference (cm) will be obtained. Skinfolds are measured with calibrated metal calipers from 7 sites (chest, calf, thigh, calf, subscapular, midaxillary, suprailiac, abdominal).

RESTING BLOOD PRESSURE (BP). BP will be measured after the participant has been sitting quietly for at least 5 minutes following standardized guidelines using a calibrated sphygmomanometer. Measurements will be repeated three times and recorded.

QUESTIONNAIRES. The following will be collected: a) The Berlin Sleep Questionnaire, b) Epworth Sleepiness Scale, c) The Sleep Habits and Medical Condition Questionnaire d) The Medical Outcomes Survey-SF 36 (MOS-SF) e) Patient Health Questionnaire-9 (PHQ-9) f) Daily ECG/Activity Log g) Atrial Fibrillation Effect on Quality-of-life, a 20-item questionnaire that assesses the impact of atrial fibrillation on quality of life.

6 Minute Walk Test. Baseline oxygen saturation and heart rate will be recorded. If oxygen saturation >90%, then proceed with protocol. Using the BORG Scale record rate the symptoms of breathlessness and leg fatigue after a 6 minute walk at usual pace.

Arterial Applanation Tonometry: Radial artery measurements will be performed after sphygmomanometric pressure is obtained with use of an applanation tonometry probe with a minimum of two consecutive measurements to obtain pulse wave analysis results. For pulse wave velocity, lead II ECG will be performed along with cardotid and femoral applanation tomometry.