Mandibular Advancement Device for Treatment of Obstructive Sleep Apnea and Its Impact on Cardiac Remodeling

The MOSAIC is a randomized, double-blind, placebo-controlled, cross-over trial to be conducted at the National University Health System. It is a collaboration between the National University Heart Centre Singapore, the Faculty of Dentistry, and the University Medicine Cluster. Apart from evaluating the effect of MAD on AHI- a conventional measure of OSA severity, the investigators will also explore the effect of MAD on cardiac remodeling. Adverse remodeling equates to progressive worsening of cardiac function, and slowing or reversing such remodeling is a goal of HF therapy. Ventricular measures including LV end diastolic volume index (LVEDVI) have proven to be meaningful surrogates reflecting the beneficial effect of therapeutic agents such as angiotensin-converting enzyme inhibitors and beta-adrenergic blocking agents on the remodeling process and on "hard" morbid and mortal end points.

Screening. Patients (n=200) will undergo polysomnography and coned beam CT if the following criteria are met: (i) Asians (Chinese, Malay or Indians) living in Singapore (ii) symptomatic HF (NYHA classes II-III) due to ischemic cardiomyopathy, (iii) LVEF <45% (as determined by echocardiography) (iv) clinical stability for ≥1 month, (v) optimal medical therapy including a diuretic, an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, and a beta-blocker. The doses of these background medications should be stable for ≥1 month. Exclusion criteria:-(i) known OSA on treatment, (ii) acute coronary syndrome within the preceding 3 months, (iii) severe valvular heart disease, (iv) sustained ventricular arrhythmia, (v) stroke with residual neurological deficits, (vi) contraindication to CMR such as a pacemaker or cardioverter-defibrillator implant.

Overnight Polysomnography will be performed at the National University Health System (NUHS) Cardiosleep Research Laboratory following a standard laboratory protocol with a computerized recording system. All sleep studies will be scored according to the American Academy of Sleep Medicine guidelines, by an experienced sleep physician. Apnea is defined as a complete cessation in airflow lasting ≥10 s and hypopnea as a reduction in airflow or thoraco-abdominal movement by ≥50% for ≥10 s. Apneas will be classified as (i) obstructive if thoraco-abdominal movement was present during the apnea; (ii) central if thoraco-abdominal movement was absent; and (iii) mixed if thoraco-abdominal movements were both present and absent during the period of airflow cessation.

Coned beam CT. To determine the specific craniofacial anatomy that predicts OSA in Asians with HFrEF, the patients (regardless of the polysomnography results) will undergo a coned beam CT for craniofacial profiling at the Faculty of Dentistry. Image acquisition will be performed during quiet tidal breathing with subjects supine and with a neutral head position. Landmarks will be identified and measurements performed as previously reported. Tongue area will be measured by tracing the contours on the sagittal plane, whereas lateral wall thickness and parapharyngeal fat will be quantified on the axial plane. To determine tongue volume, the tongue limits will be identified and traced manually on each axial image obtained. Volumetric reconstructions will be performed to determine mandible, tongue, and airway volume.

Randomization. After the initial evaluation, the patients found to have OSA (estimated prevalence 50%, n=100) with an AHI of ≥ 15 events/hr will be randomized to (i) MAD followed by sham MAD (non-advanced device) or (ii) sham MAD followed by MAD, with a 2-week washout period in between. A dentist, who is otherwise not involved in HF care, will open a sealed envelope at the time of randomization and program the MAD device accordingly. Each mode will be maintained for 3 months, with comprehensive testing (polysomnography, echo, and biomarker assays) at the end of each 3-month period. The patients would also keep a daily record of time overnight wearing the device (adherence).