Obstructive Sleep Apnea (OSA), Hypertension , β1 Subunit of Maxi-k+ Channel and Cardiovascular Risk
Condition: Obstructive Sleep Apnea
MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
Study type: Observational

Summary: 
      To describe the relationship between OSA and clinical Hypertension (performing ABPM),
      endothelial dysfunction (performing flowmetry), and its relation at the basic research
      (determining the β1 subunit in Peripheral Leukocytes in peripheral blood). This relation
      between OSA and HTA has been evaluated in basal conditions and after modifying the
      pathophysiological role of OSA applying treatment with positive continues pressure (CPAP)
      during 3 months.
    

Detailed description: 
      Background: Several epidemiological studies have demonstrated that untreated OSA with
      continuous positive airway pressure, is related to high rates of cardiovascular morbidity and
      mortality, being HTA the most important cardiovascular morbidity associated with OSA. This
      relationship has been studied at three levels: clinical, subclinical and the basic research
      or molecular level. Most patients with OSA diagnosis have developed clinical hypertension
      and, because of the high prevalence of nocturnal hypertension in OSA, it would be essential
      to monitor blood pressure during sleep, using this device ambulatory blood pressure
      monitoring (ABPM). Regard to endothelial dysfunction, which can exist before irreversible
      vascular changes have occurred in the arterial wall (subclinical level) has been reported
      that patients with OSA have lower blood flow (measured by arterial flowmetry) and after
      treatment with CPAP, there is an improvement in endothelial function. At basic research
      level, in previous studies it has been observed that hypoxia down regulates the expression of
      Maxi-K+ Channel B1-subunit in smooth muscle cell and also in peripheral leukocytes. This
      channel is involved in the regulation of arterial vasodilation, being β1 subunit responsible
      for the vascular tone regulation. Basic research studies have shown the relationship between
      hypertension and ß1 subunit, describing that the expression of that unit decreases in
      hypertensive animal models. In a pilot study in OSA patients was suggested that ß1 subunit
      channel Maxi-K + could play an important role in vascular dysregulation of these patients. It
      has been also described a correlation between ß1 subunit level in vascular smooth muscle
      cells and its level in leukocytes.

      Objective: To describe the relationship between OSA and hypertension from a clinical point of
      view (by performing ABPM), its relationship with endothelial dysfunction (by performing a
      flowmetry) and basic research level (by the determination of β1 subunit of the maxi-K channel
      +). This relationship between hypertension and OSA has been assessed at baseline condition in
      a group of OSA patients and a control group without OSA, and after changing the
      pathophysiological role of OSA treating with continuous positive pressure airway (CPAP) in
      the group of OSA patients.

      Patients: Prospective study in which:

        1. - We compared 61 patients with sleep apnea-hypopnea syndrome and 19 control subjects
           without OSA.

        2. - In the group of 61 patients with OSA: we compared the results before and after three
           months of correct treatment with CPAP.

      Measurements:

        1. - Respiratory Polygraphy

        2. - Ambulatory Blood Pressure Monitoring

        3. - Endothelial dysfunction, by determining the hyperaemic response to ischemia using a
           Laser-Doppler flowmeter.

        4. - ß1en subunit expression in peripheral blood leukocytes.

      These procedures are described below:

        1. - Respiratory Polygraphy:

           -Nocturnal cardiorespiratory polygraphy was performed in the "sleep laboratory of
           Medical-Surgical Unit of Respiratory Diseases". It has used a respiratory polygraph
           "Sibelhome plus"(trade name).

           We measured the following variables:

             -  Oronasal Flow.

             -  Snore: using laryngotracheal microphone.

             -  Thoracoabdominal-Effort: by two bands effort sensors placed at the level of the
                chest and abdomen.

             -  Arterial oxygen saturation (SaO2): Flexible digital pulse oximeter.

             -  Body-position sensor.

           The records are stored in a specific database and analysis was carried out manually. The
           events are defined

             -  Apnea: absence of oronasal airflow for ≥ 10 sec.

             -  Hypopnea: oronasal flow decrease ≥ 50% from baseline for ≥ 10 seconds, accompanied
                by desaturation.

           We calculated the following parameters:

             -  AHI: total number of apnea + hypopnea / hour check. When AHI is <5 was considered
                negative for OSA and when AHI WAS ≥ 15, OSA diagnosis was made.

             -  Desaturation index (DI): total number of desaturations / hour check.

             -  Basal and minimum-Saturation: automatic analysis obtained oximetry throughout the
                entire record.

             -  Percentage of recording time with SaO2 <90% (CT90): automatic analysis obtained
                oximetry throughout the entire record.

        2. - Ambulatory Blood Pressure Monitoring: The dispositive measures blood pressure
           automatically every 20 minutes for 24 hours. The records were obtained on a weekday and
           when the patient worked in shifts, it was made when the patients didn´t work at night.

           We collected the following variables:

             -  24hours systolic and diastolic blood pressure.

             -  Medium blood pressure at day and night.

             -  Standard deviation day and night blood pressure.

             -  Percentage of high measured for 24 hours, and during periods of activity and rest.

             -  BP variability (standard deviation of the mean).

             -  24-hour mean heart rate.

             -  Average heart rate daytime.

             -  Night Average heart rate.

        3. - Endothelial dysfunction, by determining the hyperaemic response to ischemia using a
           Laser-Doppler flowmeter: The subject lay on the bed, and kept quiet 15-20 minutes. A
           cuff blood pressure measurement (uninflated) was placed on the arm and laser-Doppler
           device in the forearm. During 15 minutes the system measured basal situation and after
           that the cuff rapidly swelled over 20mmHg of the systolic blood pressure during for 4
           minutes. During this period the system monitor showed perfusion units and at the end of
           this period the cuff was suddenly deflated and the monitor revealed a rise above the
           pre-ischemia in perfusion units.

           The software performed two types of analysis:

             -  General analysis: where reported the initial value, maximum value, percentage
                change from the first to last value or maximum slope of the curve or slope and area
                under the curve.

             -  Adjusted Analysis: It was estimated biological zero, peak flow, hyperemia area,
                time to maximum hyperemia, time to reach the half-maximal hyperemia and latency.

        4. - ß1 subunit expression in peripheral blood leukocytes: Performing the level of β1
           subunit of Maxi-K + channel expression in peripheral blood leukocytes. Extraction total
           RNA from leukocytes following the instructions QIAamp RNA Blood Mini kit.

      From these cells was performed the expression level of β1 subunit by quantitative RT-PCR
      technique. For reverse transcription of RNA using the Superscript III First-kit Starnd
      Synthesis System (trade name). For quantitative PCR we used the ABI PRISM equipment 7500
      Sequence Detection System (Applied Biosystems), using the reagents Sybr Green PCR Master Mix
      or TaqMan probes, following the protocols indicated by the manufacturer.
    

Intervention name(s): Continuous positive airway pressure (CPAP) therapy
Intervention type(s): Device
Intervention description(s): Device: CPAP accordingly to the normal therapy in daily practice. In the group of 61 patients with OSA: we compared the results before and after three months of correct treatment with CPAP.
First, an automatic continuous positive airway pressure device (autoCPAP REMstar) was used to evaluate the pressure titration by night registration at patient home. AutoCPAP gets complete information about the optimum level to be set as therapeutic (CPAP pressure).
The patient has been reevaluated periodically in the outpatient Sleep Unit to verify proper adaptation and compliance of CPAP.
We considered a proper compliance when patients used CPAP ≥ 4 hours/day. This data has been extracted from the counter included in the CPAP compressor.
Procedures:
- Respiratory Polygraphy
- Ambulatory Blood Pressure Monitoring
- Endothelial dysfunction, by determining the hyperaemic response to ischemia using a Laser-Doppler flowmeter.
- ß1en subunit expression in peripheral blood leukocytes.
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Group of OSA patients and a control group without OSA
      
Biospecimen description: 
      Periferical blood
    
Keywords: Obstructive Sleep Apnea; Hypertension; β1 Subunit of Maxi-k+Channel; Cardiovascular Risk