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.

Inclusion Criteria:

Inclusion Criteria for Cases:

PAF defined by recurrent episodes of AF, which self-terminate within a 7-day period (based
upon AHA consensus statement 77)

Age 18-80 years

Individuals able to participate in > 2 overnight/daytime sleep and physiologic assessments
over a 3 month period.

Inclusion Criteria for Controls:

Age 18 to 80 years

Individuals in normal sinus rhythm (NSR) with no current AF or history of AF

Individuals able to participate in an overnight/daytime sleep and physiologic assessment.

Exclusion Criteria:

Exclusion Criteria for Cases:

PAF with rapid or uncontrolled rate (>120bpm)

Post-operative PAF

History of cardiac ablation or successful electro-cardioversion for PAF (ablation for other
arrhythmias such as AVNRT and if PAF persists after cardioversion is acceptable )

Valvular stenosis, prosthesis or significant valvular insufficiency [i.e. those with
moderate or greater severity of aortic stenosis (aortic valve area <1.5 cm2), mitral
regurgitation which is moderate or more severe in degree (>20% regurgitant fraction) or
moderate or greater severity mitral stenosis (mitral valve area <1.5 cm2)]

Atrial septal defect

Infiltrative/restrictive cardiomyopathy

Sick sinus syndrome

Previously diagnosed SDB on specific SDB treatments (CPAP, oral appliances)

Severe chronic insomnia

Circadian rhythm disorder (e.g. shift work sleep disorder, delayed or advanced sleep phase
syndrome)

Insufficient sleep syndrome defined by reported sleep duration < 4 hrs

Supplemental oxygen use

Unstable medical conditions (e.g., new onset or changing angina, a myocardial infarction or
congestive heart failure exacerbation documented within the previous 3 months, systolic
heart failure (Left Ventricular Ejection Fraction < 35%), high grade cardiac
dysrhythmia/heart block, stroke with functional limitations, uncontrolled hypertension
(BP>170/110), abdominal aneurysm >5.5 cm or >1 cm growth/year, uncontrolled diabetes
mellitus (HbA1c>9.0), pulmonary hypertension, non-skin cancer diagnosis or treatment within
the previous year, end stage renal and hepatic failure, immunodeficiencies (HIV, HCV),
uncontrolled hypo- or hyperthyroidism)

Psychiatric disorders which are inadequately treated

Compromised competence

Alcohol abuse (currently drinks >5 alcoholic drinks/day)

Pregnancy

Inability to provide informed consent

Illicit drug use over last 6 months

Rate controlling anti-arrhythmic medication (Classes I-III and V) with no further clinical
occurrence of PAF

Has a Pacemaker or Implantable cardioverter-defibrillator.

Rationale for criteria: The goal of this study is to include those patients with PAF that
is not secondary to the post-operative period or valvular disease and without ablation as
these processes would result in alteration of atrial physiology and preclude assessment of
independent SDB effects on AF which is independent of these conditions. Patients with sleep
disorders will be excluded as sleep disorders may influence arrhythmogenesis. Those on
treatment for SDB will be excluded because treatment would preclude assessment of SDB
pathophysiologic effects on atrial arrhythmogenesis. Those with unstable medical conditions
or rapid or uncontrolled heart rate will be excluded due to safety reasons.

Note: Exclusion criteria for positive airway pressure (PAP) intervention: Central Apnea
Index>5 noted on baseline examination sleep study or evidence of Cheyne Stokes
Respirations/periodic breathing (cyclical crescendo and decrescendo change in breathing
amplitude).

Exclusion Criteria for Controls:

Current or history of AF, otherwise the same exclusion criteria listed for cases.