CPAP Therapy in Patients With Heart Failure and Obstructive Sleep Apnea.

OSA and heart failure (HF) are states of increased afterload, metabolic demand and sympathetic nervous system(SNS) activation. In patients with OSA and HF, CPAP initially may reduce LV stroke volume(SV) but subsequently improves LV function. This may relate to an early beneficial effect on myocardial energetics through early reduction in metabolic demand that subsequently leads to improved efficiency of LV contraction. However, it is not clear whether CPAP favourably affects cardiac energetics. Any such benefit may also relate to reduced SNS activation with CPAP therapy. However its effect on myocardial SN function is also not well studied. We propose to evaluate the temporal effect of CPAP on daytime 1) oxidative metabolism; 2) the WMI as an estimate of mechanical efficiency; 3) myocardial SN pre-synaptic function; and 4) HR variability in patients with OSA and HF. We will also determine whether these parameters are altered compared to a group of patients with HF without OSA. In conjunction with echocardiographic measures of LV stroke work, PET derived [11C]acetate kinetics will be used as a measure of oxidative metabolism, to determine the work metabolic index (WMI). [11C]HED retention will be used to measure cardiac SN pre-synaptic function.

HYPOTHESES

Primary Hypotheses:

In patients with chronic stable HF and OSA, 6-8 weeks' of CPAP demonstrates:

• beneficial effects on daytime myocardial metabolism leading to a reduction in the rate of oxidative metabolism as measured by [11C]acetate kinetics using PET imaging;
• improvement in energy transduction from oxidative metabolism to stroke work as measured by an increase in the daytime work-metabolic index.

Secondary Hypotheses:

In patients with chronic stable heart failure and OSA,

• CPAP leads to an early (1 week'') reduction in daytime oxidative metabolism that precedes the improvement in work-metabolic index, indicating an early energy sparing effect;
• CPAP leads to i) an increase in daytime myocardial SN pre-synaptic function as measured by increased [11C]HED retention on PET imaging, and ii) a parallel decrease in sympathetic and increase in vagal modulation of sino-atrial discharge (i.e. heart rate (HR) variability)
• there is impaired daytime myocardial oxidative metabolism, work-metabolic index, and myocardial sympathetic nerve function compared to patients with heart failure without OSA.

'original protocol indicated 1 month follow up but was changed to 6-8 weeks in order to accommodate patient logistics and imaging centre scheduling.

''Logistics did not permit all patients to complete 1 week scan.

Inclusion criteria

• systolic LV dysfunction (LVEF<40%; by echocardiography, radionuclide or contrast ventriculography)
• symptoms of HF: NYHA Class II to III
• stable condition with optimally tolerated medical therapy, unchanged for > 4 weeks
• Obstructive sleep apnea (OSA) diagnosed on nocturnal polysomnogram with an apnea/hypopnea index (AHI) >15 events/hr and a predominantly obstructive pattern(more than 80% of events being obstructive in nature)OR
• no OSA: defined as AHI<5 (control subjects) will be matched with the OSA group for gender, age + 5 years, ejection fraction (EF) +5%, drug therapy and etiology of HF (ischemic or non-ischemic)
• willingness to receive CPAP therapy
• informed consent

Exclusion criteria

• unstable angina or recent myocardial infarction (MI) (<4 weeks prior)
• severe valvular dysfunction
• requirement for revascularization
• a permanent pacemaker
• atrial fibrillation
• significant ventricular arrhythmia or sinus node dysfunction
• life expectancy less than 1 year due to other co-morbidity
• significant restrictive and obstructive lung disease
• concomitant treatment or use of: tricyclic antidepressants, cocaine or drugs which may alter catecholamine uptake; or hypnotic, benzodiazepine, selective serotonin reuptake inhibitors(SSRI), neuroleptic, narcotic or other medications which may alter sleep or sleep-disordered breathing
• central sleep apnea
• other primary sleep disorder (i.e. periodic limb movement with arousal >5 events/hr, narcolepsy, rapid eye movement (REM) behaviour disorder)
• requiring supplemental oxygen therapy at night
• debilitating daytime somnolence (indicating clear-cut indication for CPAP therapy)
• a previous cardiac transplant
• a large transmural scar defined on previous perfusion imaging(severe resting perfusion defect (<50% uptake) occupying >25% of the LV)148-150
• age < 18 years
• pregnant or breast-feeding