search
Back to results

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

Primary Purpose

Heart Failure, Obstructive Sleep Apnea, Central Sleep Apnea

Status
Active
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
[C11]Acetate and HED PET
Sponsored by
Ottawa Heart Institute Research Corporation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Heart Failure focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

This study (AMEND) is a single centre substudy of the ADVENT-HF trial (NCT01128816). ADVENT-HF is a RCT that will test the effects of ASV on morbidity and mortality in patients with HF and OSA or CSA.

The AMEND 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

Inclusion Criteria:

  1. American Heart Association (AHA) Stages B, C and D heart failure due to ischemic, idiopathic or hypertensive causes with;
  2. systolic dysfunction, ejection fraction (EF) ≤45% by echocardiography
  3. optimal medical therapy conforming to the AHA guidelines (and for this proposal, stable therapy for >4 weeks)
  4. 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
  5. age >18 years;
  6. willingness to receive ASV therapy
  7. informed consent

Exclusion Criteria:

  1. Myocardial infarction, cardiac surgery or angioplasty within 3 months prior to enrollment,
  2. listed for heart transplantation,
  3. HF due to primary valvular heart disease,
  4. pregnancy
  5. current use of ASV or CPAP.
  6. awaiting revascularization;
  7. previous cardiac transplant;
  8. life expectancy less than 6 months due to other co-morbidity;
  9. a large transmural scar defined on previous perfusion imaging (severe resting perfusion defect (<50% uptake) occupying >25% of the LV);
  10. 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 sub-study

Sites / Locations

  • University of Ottawa Heart Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

[C11]Acetate HED PET

Arm Description

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.

Outcomes

Primary Outcome Measures

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
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.

Secondary Outcome Measures

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

Full Information

First Posted
April 14, 2014
Last Updated
October 11, 2022
Sponsor
Ottawa Heart Institute Research Corporation
search

1. Study Identification

Unique Protocol Identification Number
NCT02116140
Brief Title
ASV Effects on Myocardial Energetics and Sympathetic Nerve Function in Heart Failure and Sleep Apnea.
Acronym
AMEND
Official Title
Effects of Long Term Adaptive Servo Ventilation Therapy on Myocardial Energetics and Sympathetic Nerve Function in Heart Failure and Sleep Apnea. The AMEND Sub-study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 2012 (undefined)
Primary Completion Date
June 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ottawa Heart Institute Research Corporation

4. Oversight

Data Monitoring Committee
No

5. Study Description

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: 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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
[C11]Acetate HED PET
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
[C11]Acetate and HED PET
Primary Outcome Measure Information:
Title
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
Time Frame
6 months
Title
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
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,
Time Frame
6 months
Title
ASV for CSA or OSA in patients with HF and sleep apnea will normalize daytime sympathetic contributions to heart rate variability
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
This study (AMEND) is a single centre substudy of the ADVENT-HF trial (NCT01128816). ADVENT-HF is a RCT that will test the effects of ASV on morbidity and mortality in patients with HF and OSA or CSA. The AMEND 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 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, 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 Exclusion Criteria: 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. 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 sub-study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rob S Beanlands, MD
Organizational Affiliation
Ottawa Heart Institute Research Corporation
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Ottawa Heart Institute
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1Y 4W7
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
11044422
Citation
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.
Results Reference
background
PubMed Identifier
17258090
Citation
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.
Results Reference
background

Learn more about this trial

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

We'll reach out to this number within 24 hrs