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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.
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".
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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) |
|
| 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) |
|
| 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Static Handgrip | Other | Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cardiac Beta-receptor Sensitivity | Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level. | 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. | 1 day; primary outcome was complete for each subject in 1 day |
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Healthy Controls
Inclusion Criteria:
Exclusion Criteria:
HFpEF Subjects
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Benjamin D Levine, MD | University of Texas Southwestern Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Institute for Exercise and Environmental Medicine | Dallas | Texas | 75231 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32164435 | Derived | 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. |
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Recruitment initiated in June 2015 and completed October 2017. Subjects were recruited from academic medical center cardiology clinic. Healthy control subjects were recruited from the community.
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| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Seniors | 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. Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
| FG001 | HFpEF | 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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
| FG002 | Healthy Young | 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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Seniors | 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. Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cardiac Beta-receptor Sensitivity | Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level. | Posted | Mean | Standard Deviation | beats per ng/kg/min ISO | 1 day; primary outcome was complete for each subject in 1 day |
|
2 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Healthy Seniors | 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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Satyam Sarma | University of Texas Southwestern Medical Center | 214-345-7111 | SatyamSarma2@texashealth.org |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 1, 2014 | Apr 4, 2019 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| D006024 | Glycopyrrolate |
| D007545 | Isoproterenol |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Dexmedetomidine | Drug | 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. |
|
|
| Glycopyrrolate | Drug | 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. |
|
|
| Isoproterenol | Drug | 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. |
|
|
| BG001 | HFpEF | 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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
| BG002 | Healthy Young | 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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Two senior controls, three young controls and two HFpEF subjects withdrew consent. | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Two senior controls, three young controls and two HFpEF subjects withdrew consent. | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Two senior controls, three young controls and two HFpEF subjects withdrew consent. | Count of Participants | Participants |
|
| Race (NIH/OMB) | Two senior controls, three young controls and two HFpEF subjects withdrew consent. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Exercise heart rate | Two senior control, three young control and two HFPEF subjects withdrew after consent. | Mean | Standard Deviation | beats per minute |
|
| Beta-receptor function | Two senior controls, three young controls and two HFpEF subjects withdrew consent | Mean | Standard Deviation | beats per ng/kg/min |
|
| OG001 | HFpEF | 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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
| OG002 | Healthy Young | 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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. |
|
|
| Primary | 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. | Young subjects did not perform handgrip portion of the study. | Posted | Mean | Standard Deviation | beats per minute | 1 day; primary outcome was complete for each subject in 1 day |
|
|
|
| 0 |
| 13 |
| 0 |
| 13 |
| 0 |
| 13 |
| EG001 | HFpEF | 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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. | 0 | 13 | 0 | 13 | 0 | 13 |
| EG002 | Healthy Young | 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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion. | 0 | 7 | 0 | 7 | 0 | 7 |
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| D000644 |
| Quaternary Ammonium Compounds |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D009861 | Onium Compounds |
| D011759 | Pyrrolidines |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D002395 | Catecholamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|