Long QT Syndrome and Sleep Apnea

Potential participants will come to the Cleveland Clinic Clinical Research Unit (CRU) for
informed consent, eligible participants will undergo a 12 lead electrocardiogram. If the
participants is found to have long QT syndrome (QTc ≥ 450 in men ad ≥ 470 in women) the
participant will continue on in the study. If the participant is found to not have long QT
syndrome the participant will exit the study. If continuing on in the study the participant
will undergo a fasting venipuncture and blood pressure measurements. The participant will
then be shown how to use the portable sleep study hook-up and continuous 12-lead ECG
monitoring to be monitored in the home setting. The sleep study and ECG monitors will be
returned by a courier service the next morning.

Those participants who are identified to have OSA (apnea hypopnea index>5, estimate 50% of
those recruited) on the portable sleep monitoring will be invited to wear CPAP for 2-3 months
with a follow up visit with repeat portable polysomnographic and continuous
electrophysiologic assessments and CRU visit for bloodwork and blood pressure.

DATA COLLECTION Portable Polysomnography The Embletta Gold ® is a battery-operated device
that can sample data at a 1000 Hz sampling rate and store data at 200 Hz, with 1 GB of
storage capacity allowing storage of data from up to 20-24 hrs of recording. The device
contains the critical sensors which are recommended by the American Academy of Sleep Medicine
as validated sensors for measuring OSA: nasal pressure/flow; thoracic and abdominal
inductance plethysmography (effort); and finger pulse oximetry (oxygen saturation).

Relevant PSG Variables: A registered polysomnologist will score the sleep study data. Apneas
will be classified as "central" or "obstructive" according to the absence or presence of
respiratory effort respectively. Hypopneas will be scored as a 50% amplitude reduction in
inductance or flow and associated 3% oxygen desaturation or arousal. Periodic breathing will
be defined as airflow or inductance channels increasing and decreasing at least 50% from the
maximum, in a cyclic waxing and waning or "sinusoidal" manner for a consecutive period of >10
min.

Continuous Overnight 12-lead ECG Monitoring CardioDay Holter (GE) monitoring reads SEER 12
data and exports Holter data as individual 10 second, 12 lead reports up to six per minute,
i.e. all recorded data. The monitor is capable of continuous 12-lead ECG monitoring with the
ability to record up to 10 days with Bluetooth ® technology and 12-bit signal resolution with
up to 1024 sampling rate.

ECG Sensor Application. This will be performed by a trained research coordinator at the visit
in tandem with sleep monitor lead hook-up. Participants will be asked to remove clothing from
the waist up to attach the sensors to the chest. Staff will ensure privacy by covering the
participant with a sheet or gown. The staff will shave necessary areas on the chest prior to
sensor application to ensure that the sensors stick closely to the skin and will provide the
participant with the ECG monitor/holster/clip, leads, communicator and charger, electrodes
and a handbook with simple pictorial/written educational instructions. A research coordinator
will be available by phone 24-7 to address issues with device malfunction, lead placement and
replacement of equipment. ECG quality grade data will be collected: (excellent: >90% of ECG
data without artifact, good: 70-90% without artifact, fair: 50-70% without artifact, poor
<50% artifact free).

Relevant ECG Variables. Standard average QT interval measures will be obtained with eventual
ability to examine peri-apneic and peri-hypopneic alterations in QT interval. Novel QT
morphologic assessments will be made with the GE compatible platform described below.

Novel QT analysis platform An analysis system which enables biopharmaceutical companies to
analyze detailed morphology of the electrocardiography (ECG) T-wave (QT Guard Plus™,
eResearchTechnology, Inc.). The system identifies and quantifies characteristic changes in
the shape of the T-wave found in drugs that produce Torsades de Pointes (TdP), the latter a
potentially lethal tachyarrhythmia. QT Guard Plus imports individual 10 second, 12 lead
reports for analysis and parameter extraction, i.e. T wave shape measures with the capability
to extract other electrophysiologic signatures as well.

Resting Blood Pressure BP will be measured after the participant has been sitting quietly for
at least 5 minutes following standardized guidelines using a calibrated sphygmomanometer.
Cuff size will be determined by measuring the circumference of the upper arm, measured at the
midpoint and identifying the appropriate bladder size from a standard chart. Measurements
will be repeated three times and recorded.

Fasting Venipuncture Phlebotomy (40cc) will be performed the morning of the baseline and
follow-up visits using standard techniques by trained research staff following written
procedures (e.g., pre-labeled bar coded tubes, minimizing trauma, etc.). The sample will be
divided into tubes for the varied analyses (20 mL clot for serum, 20 mL EDTA). Clots will be
centrifuged and the serum removed within 1 hr of venipuncture. Plasma from EDTA samples will
be stored for future DNA analysis. Assays will be stored in dedicated, alarmed freezers at
-80°C in the CRU Core Lab and transferred to designated space in the Pathology and Laboratory
Medicine Institute.

Morning blood work to examine the association of electrolytes in relation to QT interval
duration and stability upon follow up after use of CPAP. With collateral funding, bloodwork
will allow for examination of markers of systemic inflammation which may serve as
intermediary pathways for cardiac electrophysiologic biomarkers of VTA in OSA.

Continuous Positive Airway Pressure Intervention Participants randomized to CPAP will be
provided with an Autopap REMstar device (Philips-Respironics, Inc, Murrysville, PA) with
integrated humidifier, set at a pressure range of 4-20 cm H2O, with auto-titration according
to the device's algorithm for detecting airflow limitation which provided wireless
transmission of usage information to our research team.

Inclusion Criteria:

- Clinical diagnosis of QT prolongation as described above

- Age 18-75 years

- Individuals able to participate in at least 2 overnight sleep and hysiologic
assessments over a 3 month period.

Exclusion Criteria:

- Use of specific OSA treatments (CPAP, oral appliances)

- Use of supplemental oxygen

- 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 hours

- Unstable medical conditions (e.g., new onset or changing angina, a myocardial
infarction or congestive heart failure exacerbation documented within the previous 3
months, uncontrolled hypertension (BP>170/110), uncontrolled diabetes mellitus
(HbA1c>9.0), uncontrolled hypo- or hyperthyroidism)

- Psychiatric disorders which are inadequately treated

- Compromised competence

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

- Inability to provide informed consent

- Illicit drug use over last 6 months.

Rationale for criteria:

Patients with sleep disorders will be excluded as other sleep disorders may influence
arrhythmogenesis.

Those on treatment for SDB will be excluded because treatment would preclude assessment of
OSA pathophysiologic effects on QT biomarkers.

Those with unstable medical conditions or rapid or uncontrolled heart rate will be excluded
due to safety reasons.