Heart FailureNCT02524145
Chronotropic Incompetence in Patients With HFpEF
A study testing Static Handgrip, Dexmedetomidine and Glycopyrrolate in people with Heart Failure, run by University of Texas Southwestern Medical Center at 1 site in United States.
Trial summary
The purpose of this study is to determine the mechanisms of chronotropic incompetence (inability to increase heart rate with exercise) in patients with heart failure and preserved ejection fraction (HFpEF). Read more about this study
- Who is it for?
- Ages 18 to 85 yearsHealthy volunteers can take part
- Conditions the study is for
- Heart Failure
- What is being tested?
- Static Handgrip, Dexmedetomidine and Glycopyrrolate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2015to 15 Nov 2017
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- ages > 60 years
- body mass index <30
- absence of co-morbid conditions including hypertension, diabetes, heart failure, asthma, chronic obstructive pulmonary disease, coronary artery disease as evidenced by angina or prior myocardial infarction or cerebrovascular disease as evidenced by prior transient ischemic attack or stroke
- Patients will be > 60 years old, male or female, all races.
- signs and symptoms of heart failure
- ejection fraction > 0.50
- objective evidence of diastolic dysfunction.
- All patients must be in sinus rhythm without a left bundle branch block at the time of study
Who cannot join
- ages less than 60
- body mass index >30
- presence of co-morbid conditions including hypertension, diabetes, heart failure, asthma, chronic obstructive pulmonary disease, coronary artery disease as evidenced by angina or prior myocardial infarction or cerebrovascular disease as evidenced by prior transient ischemic attack or stroke
- Patients with chronic orthopedic injury that might make them unable to participate in an exercise testing will also be excluded
- Subjects unable to speak English will not be recruited because of the complex experimental studies and the need for precise communication between the volunteers and the research staff to ensure safety.
- HFpEF Subjects
Show all 15Show fewer
- underlying valvular or congenital heart disease
- restrictive or infiltrative cardiomyopathy
- acute myocarditis
- New York Heart Association (NYHA) Class IV congestive heart failure, or heart failure that cannot be stabilized on medical therapy
- other condition that would limit the patient's ability to complete the protocol
- manifest ischemic heart disease
- Coumadin/warfarin therapy
- Patients with chronic orthopedic injury that might make them unable to participate in an exercise testing will also be excluded
- Subjects unable to speak English will not be recruited because of the complex experimental studies and the need for precise communication between the volunteers and the research staff to ensure safety.
Trial locations and contacts
1 site in 1 country.
United States1 site
The Institute for Exercise and Environmental Medicine
Dallas, Texas, 75231
About this study
Official title: Determinants of Chronotropic Incompetence in Patients With Heart Failure and a Preserved Ejection Fraction (HFpEF)
The purpose of this study is to determine the mechanisms of chronotropic incompetence (inability to increase heart rate with exercise) in patients with heart failure and preserved ejection fraction (HFpEF). The investigators will test both central command regulation and cardiac beta-receptor sensitivity over control of heart rate.
Read the detailed description
About half of all elderly patients with a diagnosis of congestive heart failure have apparently normal systolic function, so called "heart failure with a preserved ejection fraction" or HFpEF. To date, no effective therapy for HFpEF has been found, in part because of failure to discern key pathophysiologic pathways.
Although HFpEF is a complex disease with multiple pathophysiologic pathways leading to the phenotype of heart failure, virtually all proposed mechanisms involve some impairment of diastolic function - the inability of the heart to fill adequately at a low enough pressure to avoid congestion which during physical activity or exercise, prevent an increase in heart rate. A number of studies have purported the inability to increase heart rate (chronotropic incompetence) is responsible for the diminished exercise capacity.
Alternatively, the investigators hypothesize that the stiff, slowly relaxing heart of patients with HFpEF causes a marked elevation in pulmonary capillary pressure during exercise which leads to premature fatigue prior to achieving maximal heart rate, thus causing apparent "chronotropic incompetence".
- Conditions
- Heart Failure
- Being tested
- Static Handgrip, Dexmedetomidine, Glycopyrrolate, Isoproterenol
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Static HandgripOther
Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.
DexmedetomidineDrug
Also called Sympathetic blockade
Subjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline.
GlycopyrrolateDrug
Also called Parasympathetic blockade
Subjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline.
IsoproterenolDrug
Also called Beta-receptor sensitivity testing
Subjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline.
| Study group | Role | What they receive |
|---|---|---|
| Healthy Seniors | Active comparator | Fifteen healthy senior volunteers > 60 years of age. Subjects will be healthy with no chronic medical problems and on no cardiac medications except for statins. All control subjects will have a Body Mass Index (BMI) <30, with exercise histories of less than 3 days per week of aerobic exercise.
Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) Receives: Other: Static Handgrip; Drug: Dexmedetomidine; Drug: Glycopyrrolate; Drug: Isoproterenol |
| HFpEF | Experimental | Patients with HFpEF will provide data from their cardiologist or primary care physician that confirm the following: a) signs and symptoms of heart failure; b) an ejection fraction > 0.50; and c) objective evidence of diastolic dysfunction.
Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) Receives: Other: Static Handgrip; Drug: Dexmedetomidine; Drug: Glycopyrrolate; Drug: Isoproterenol |
| Healthy Young | Active comparator | Fifteen volunteers <45 yrs will be enrolled. Subjects will be healthy with no chronic medical problems and on no cardiac medications except for statins and have BMI <30.
Intervention: Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) Receives: Drug: Dexmedetomidine; Drug: Glycopyrrolate; Drug: Isoproterenol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cardiac Beta-receptor Sensitivity
Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level.
Measured: 1 day; primary outcome was complete for each subject in 1 day
Central Command Regulation of Heart Rate
Heart rate response to static hand grip immediately followed by supra-systolic arm occlusion and release will determine adequacy on central command control over heart rate response during exercise.
Measured: 1 day; primary outcome was complete for each subject in 1 day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2015 (estimated)
- Study startJun 2015
- Primary completion15 Nov 2017
- Study completion15 Nov 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Benjamin Levine, University of Texas Southwestern Medical Center
- Investigators
- Benjamin D Levine, MD, Principal investigator, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02524145
- Sponsor's protocol ID
- STU 092012-010
- Status last verified
- Aug 2020
- First submitted
- 10 Aug 2015
- Last updated
- 6 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Sarma S, Stoller D, Hendrix J, Howden E, Lawley J, Livingston S, Adams-Huet B, Holmes C, Goldstein DS, Levine BD. Mechanisms of Chronotropic Incompetence in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2020 Mar;13(3):e006331. doi: 10.1161/CIRCHEARTFAILURE.119.006331. Epub 2020 Mar 13.
PubMed 32164435
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Determinants of Chronotropic Incompetence in Patients With Heart Failure and a Preserved Ejection Fraction (HFpEF)
- ClinicalTrials.gov ID
- NCT02524145
- Acronym / sponsor ID
- STU 092012-010
- Conditions
- Heart Failure
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- University of Texas Southwestern Medical CenterUniversity, hospital or other
- Study start
- Jun 2015
- Primary completion
- 15 Nov 2017 (actual)
- Study completion
- 15 Nov 2017 (actual)
- First posted
- 14 Aug 2015 (estimated)
- Results
- Posted 23 Apr 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine the mechanisms of chronotropic incompetence (inability to increase heart rate with exercise) in patients with heart failure and preserved ejection fraction (HFpEF). The investigators will test both central command regulation and cardiac beta-receptor sensitivity over control of heart rate.
Detailed description
About half of all elderly patients with a diagnosis of congestive heart failure have apparently normal systolic function, so called "heart failure with a preserved ejection fraction" or HFpEF. To date, no effective therapy for HFpEF has been found, in part because of failure to discern key pathophysiologic pathways.
Although HFpEF is a complex disease with multiple pathophysiologic pathways leading to the phenotype of heart failure, virtually all proposed mechanisms involve some impairment of diastolic function - the inability of the heart to fill adequately at a low enough pressure to avoid congestion which during physical activity or exercise, prevent an increase in heart rate. A number of studies have purported the inability to increase heart rate (chronotropic incompetence) is responsible for the diminished exercise capacity.
Alternatively, the investigators hypothesize that the stiff, slowly relaxing heart of patients with HFpEF causes a marked elevation in pulmonary capillary pressure during exercise which leads to premature fatigue prior to achieving maximal heart rate, thus causing apparent "chronotropic incompetence".
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Healthy Seniors | Active comparator | Other: Static Handgrip, Drug: Dexmedetomidine, Drug: Glycopyrrolate, Drug: IsoproterenolFifteen healthy senior volunteers > 60 years of age. Subjects will be healthy with no chronic medical problems and on no cardiac medications except for statins. All control subjects will have a Body Mass Index (BMI) <30, with exercise histories of less than 3 days per week of aerobic exercise. Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) |
| HFpEF | Experimental | Other: Static Handgrip, Drug: Dexmedetomidine, Drug: Glycopyrrolate, Drug: IsoproterenolPatients with HFpEF will provide data from their cardiologist or primary care physician that confirm the following: a) signs and symptoms of heart failure; b) an ejection fraction > 0.50; and c) objective evidence of diastolic dysfunction. Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) |
| Healthy Young | Active comparator | Drug: Dexmedetomidine, Drug: Glycopyrrolate, Drug: IsoproterenolFifteen volunteers <45 yrs will be enrolled. Subjects will be healthy with no chronic medical problems and on no cardiac medications except for statins and have BMI <30. Intervention: Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- ages > 60 years
- body mass index <30
- absence of co-morbid conditions including hypertension, diabetes, heart failure, asthma, chronic obstructive pulmonary disease, coronary artery disease as evidenced by angina or prior myocardial infarction or cerebrovascular disease as evidenced by prior transient ischemic attack or stroke
- Patients will be > 60 years old, male or female, all races.
- signs and symptoms of heart failure
Key exclusion criteria (15 listed)
- ages less than 60
- body mass index >30
- presence of co-morbid conditions including hypertension, diabetes, heart failure, asthma, chronic obstructive pulmonary disease, coronary artery disease as evidenced by angina or prior myocardial infarction or cerebrovascular disease as evidenced by prior transient ischemic attack or stroke
- Patients with chronic orthopedic injury that might make them unable to participate in an exercise testing will also be excluded
- Subjects unable to speak English will not be recruited because of the complex experimental studies and the need for precise communication between the volunteers and the research staff to ensure safety.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Static HandgripSubjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. | Other | HFpEF, Healthy Seniors |
| DexmedetomidineAlso: Sympathetic blockadeSubjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline. | Drug | HFpEF, Healthy Seniors, Healthy Young |
| GlycopyrrolateAlso: Parasympathetic blockadeSubjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline. | Drug | HFpEF, Healthy Seniors, Healthy Young |
| IsoproterenolAlso: Beta-receptor sensitivity testingSubjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline. | Drug | HFpEF, Healthy Seniors, Healthy Young |
Primary outcome
Cardiac Beta-receptor Sensitivity
Time frame: 1 day; primary outcome was complete for each subject in 1 day
Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level.
Central Command Regulation of Heart Rate
Time frame: 1 day; primary outcome was complete for each subject in 1 day
Heart rate response to static hand grip immediately followed by supra-systolic arm occlusion and release will determine adequacy on central command control over heart rate response during exercise.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32164435Sarma S, Stoller D, Hendrix J, Howden E, Lawley J, Livingston S, Adams-Huet B, Holmes C, Goldstein DS, Levine BD. Mechanisms of Chronotropic Incompetence in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2020 Mar;13(3):e006331. doi: 10.1161/CIRCHEARTFAILURE.119.006331. Epub 2020 Mar 13.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Benjamin D Levine, MD principal investigator
University of Texas Southwestern Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Static Handgrip, Dexmedetomidine and Glycopyrrolate in people with Heart Failure, run by University of Texas Southwestern Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cardiac Beta-receptor Sensitivity (time frame: 1 day; primary outcome was complete for each subject in 1 day). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02524145, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2020.