ASV Effects on Myocardial Energetics and Sympathetic Nerve Function in Heart Failure and Sleep Apnea. (AMEND)

  • End date
    Dec 3, 2022
  • participants needed
  • sponsor
    Ottawa Heart Institute Research Corporation
Updated on 3 June 2022
continuous positive airway pressure
medical therapy
ejection fraction
heart failure
systolic dysfunction
sleep disorders
sleep disorder
obstructive sleep apnea
adaptive servo-ventilation
excessive daytime sleepiness
central sleep apnea


Obstructive sleep apnea (OSA), central sleep apnea (CSA) and heart failure (HF) are states of metabolic demand and sympathetic nervous system (SNS) activation. In patients with sleep apnea and HF, continuous positive airway pressure (CPAP) initially may reduce left ventricular (LV)stroke volume (SV) but subsequently improves and 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 long-term adaptive servo-ventilation (ASV) favorably affects cardiac energetics. Any such benefit may also relate to reduced sympathetic nervous system (SNS) activation. However its effect on myocardial SNS function is also not well studied.

In a pilot study we demonstrated early (6 week) beneficial effects of CPAP in patients with OSA and HF. The current proposal (AMEND) is a unique substudy of the recently funded ADVENT-HF trial (Adaptive Servo Ventilation for Therapy of Sleep Apnea in HeartFailure) (NCT01128816; CIHR; D. Bradley, PI).

We propose to evaluate the long-term (6 month) effects of ASV on daytime 1) oxidative metabolism; 2) the work metabolic index (WMI) as an estimate of mechanical efficiency; 3) myocardial sympathetic nerve (SN) pre-synaptic function; and 4) heart rate (HR) variability in patients with HF and coexisting OSA or CSA. In conjunction with echocardiographic measures of LV stroke work, positron emission tomography (PET) derived [11C] acetate kinetics will be used as a measure of oxidative metabolism, to determine the WMI. [11C] hydroxyephedrine (HED) retention will be used to measure cardiac SN pre-synaptic function.

Primary Hypotheses: In patients with chronic stable HF and CSA or OSA without excessive daytime sleepiness (EDS), long-term (6-month) ASV therapy yields:

  1. 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;
  2. Improvement in energy transduction from oxidative metabolism to stroke work as measured by an increase in the daytime work-metabolic index.


DEFINITIONS Obstructive sleep apnea (OSA) is characterized by: episodes of partial or complete pharyngeal collapse leading to obstructive hypopnea and apnea during sleep. OSA often coexists with HF.

Central sleep apnea (CSA) is characterized by: reductions in central respiratory drive during sleep that leads to episodes of partial or complete cessation of airflow. CSA often co-exists with HF.

Continuous positive airway pressure(CPAP) delivers air through a nasal or oral interface to preserve upper airway patency. It is a treatment for symptomatic OSA or some patients with CSA.

Adaptive Servoventilation (ASV) is effective in alleviating OSA and CSA. It provides expiratory positive pressure to alleviate OSA, and inspiratory positive airway pressure to eliminate CSA.

Oxidative metabolism: utilization of substrates via the tricarboxylic acid cycle for Adenosine triphosphate (ATP) production; it is linked to myocardial oxygen consumption and can be measured with [11C]acetate PET.

The work-metabolic index (WMI) is the external work (minute-work) of the left ventricle corrected for the rate of oxidative metabolism and is an estimate of mechanical efficiency.

Myocardial sympathetic neuron (SN) presynaptic function is the measure of uptake and storage of neuronal catecholamines in the heart measured by [11C]hydroxyephedrine (HED) PET.

Condition Heart Failure, Obstructive Sleep Apnea, Central Sleep Apnea
Treatment [C11]Acetate and HED PET
Clinical Study IdentifierNCT02116140
SponsorOttawa Heart Institute Research Corporation
Last Modified on3 June 2022


Yes No Not Sure

Inclusion Criteria

American Heart Association (AHA) Stages B, C and D heart failure due to ischemic
idiopathic or hypertensive causes with
systolic dysfunction, ejection fraction (EF) ≤45% by echocardiography
optimal medical therapy conforming to the AHA guidelines (and for this proposal
age >18 years
stable therapy for >4 weeks)
willingness to receive ASV therapy
sleep apnea with an Apnea/hypopnea Index ≥15, which will be divided into OSA (> 50%
informed consent
events obstructive), or CSA (> 50% of events central in nature)for patients with OSA
an Epworth Sleepiness Scale score of >10 and no or mild daytime sleepiness (by the
International Classification of Sleep Disorders

Exclusion Criteria

listed for heart transplantation
HF due to primary valvular heart disease
current use of ASV or CPAP
Myocardial infarction, cardiac surgery or angioplasty within 3 months prior to
awaiting revascularization
previous cardiac transplant
life expectancy less than 6 months due to other co-morbidity
a large transmural scar defined on previous perfusion imaging (severe resting
perfusion defect (<50% uptake) occupying >25% of the LV)
concomitant treatment or use of: tricyclic antidepressants, cocaine or drugs which may
alter catecholamine uptake
For heart rate variability (HRV) analysis additional exclusions will include: a) a
permanent pacemaker; b) atrial fibrillation; c) significant ventricular arrhythmia or sinus
node dysfunction; patients may be excluded from HRV analysis and still be eligible for the
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