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

NCT02116140 | Active Not Recruiting

• 2 other identifiers: 2011469-01NA7158
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Heart Failure; Obstructive Sleep Apnea; Central Sleep Apnea

Keywords

positron emission tomography; [11C]hydroxyephedrine (HED); [11C]acetate; Adaptive Servoventilation (ASV); Myocardial Energetics; work-metabolic index (WMI); Myocardial sympathetic neuron (SN) presynaptic function continuous positive airway pressure; heart rate variability; overnight polysomnogram; Plasma Norepinephrine; Urine Normetanephrine; Quality of Life

Outcome Measures

Primary Outcomes (2)

• ASV therapy yields a reduction in the rate of oxidative metabolism as measured by [11C]acetate kinetics using PET imaging in patients with HF, OSA and/or CSA

  6 months

• ASV therapy yields an improvement in energy transduction from oxidative metabolism to stroke work as measured by an increase in the daytime work-metabolic index inpatients with HF, OSA and/or CSA.

  6 months

Secondary Outcomes (2)

• ASV for CSA or OSA in patients with HF and sleep apnea will normalize daytime myocardial SN pre-synaptic function measured by [11C]HED retention on PET imaging,

  6 months

• ASV for CSA or OSA in patients with HF and sleep apnea will normalize daytime sympathetic contributions to heart rate variability

  6 months

Study Arms (1)

[C11]Acetate HED PET

EXPERIMENTAL

AMEND is a single centre substudy of the ADVENT-HF trial. This substudy is a clinical physiologic proposal designed to determine the effects of long-term (6 months) ASV on cardiac energetics and SN function in patients with chronic stable HF and sleep apnea extending our previous evaluation of short-term CPAP in patients with OSA and HF. All subjects consenting to the ADVENT primary trial will be eligible to participate in the substudy. Substudy consenting patients will have \[11C\]acetate and \[11C\]HED PET imaging; HR variability; plasma norepinephrine (NE) levels, urine normetanephrine levels within 2 weeks of the sleep study. Baseline measurements will be repeated after 6 months in all patients.

Other: [C11]Acetate and HED PET

Interventions

[C11]Acetate and HED PET OTHER

[C11]Acetate HED PET

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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, stable therapy for \>4 weeks)
• sleep apnea with an Apnea/hypopnea Index ≥15, which will be divided into OSA (\> 50% 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
• age \>18 years;
• willingness to receive ASV therapy
• informed consent

You may not qualify if:

• Myocardial infarction, cardiac surgery or angioplasty within 3 months prior to enrollment,
• listed for heart transplantation,
• HF due to primary valvular heart disease,
• pregnancy
• current use of ASV or CPAP.
• 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.

Sponsors & Collaborators

• Ottawa Heart Institute Research Corporation: lead

Study Sites (1)

University of Ottawa Heart Institute

Ottawa, Ontario, K1Y 4W7, Canada

Location

Related Publications (2)

• Beanlands RS, Nahmias C, Gordon E, Coates G, deKemp R, Firnau G, Fallen E. The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: A double-blind, placebo-controlled, positron-emission tomography study. Circulation. 2000 Oct 24;102(17):2070-5. doi: 10.1161/01.cir.102.17.2070.

  PMID: 11044422 BACKGROUND

• Yoshinaga K, Burwash IG, Leech JA, Haddad H, Johnson CB, deKemp RA, Garrard L, Chen L, Williams K, DaSilva JN, Beanlands RS. The effects of continuous positive airway pressure on myocardial energetics in patients with heart failure and obstructive sleep apnea. J Am Coll Cardiol. 2007 Jan 30;49(4):450-8. doi: 10.1016/j.jacc.2006.08.059.

  PMID: 17258090 BACKGROUND

MeSH Terms

Conditions

Heart Failure; Sleep Apnea, Obstructive; Sleep Apnea, Central

Interventions

carbon-11 acetate

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Sleep Apnea Syndromes; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases

Study Officials

• Rob S Beanlands, MD

  Ottawa Heart Institute Research Corporation

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2014
• First Posted: April 16, 2014
• Study Start: July 1, 2012
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: November 20, 2025

Record last verified: 2025-11

Locations

CA (1)