Chronotropic Incompetence in Patients With HFpEF
Study Details
Study Description
Brief 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). The investigators will test both central command regulation and cardiac beta-receptor sensitivity over control of heart rate.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: 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) |
Other: Static Handgrip
Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.
Drug: Dexmedetomidine
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.
Other Names:
Drug: Glycopyrrolate
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.
Other Names:
Drug: Isoproterenol
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.
Other Names:
|
| Experimental: 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) |
Other: Static Handgrip
Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.
Drug: Dexmedetomidine
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.
Other Names:
Drug: Glycopyrrolate
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.
Other Names:
Drug: Isoproterenol
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.
Other Names:
|
| Active Comparator: 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) |
Drug: Dexmedetomidine
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.
Other Names:
Drug: Glycopyrrolate
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.
Other Names:
Drug: Isoproterenol
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Cardiac Beta-receptor Sensitivity [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 [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.
Eligibility Criteria
Criteria
Healthy Controls
Inclusion Criteria:
-
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
Exclusion Criteria:
-
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
Inclusion Criteria:
-
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
Exclusion Criteria:
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The Institute for Exercise and Environmental Medicine | Dallas | Texas | United States | 75231 |
Sponsors and Collaborators
- University of Texas Southwestern Medical Center
Investigators
- Principal Investigator: Benjamin D Levine, MD, University of Texas Southwestern Medical Center
Study Documents (Full-Text)
More Information
Publications
None provided.- STU 092012-010
Study Results
Participant Flow
| Recruitment Details | 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. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Healthy Seniors | HFpEF | Healthy Young |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. |
| Period Title: Overall Study | |||
| STARTED | 15 | 15 | 10 |
| COMPLETED | 13 | 13 | 7 |
| NOT COMPLETED | 2 | 2 | 3 |
Baseline Characteristics
| Arm/Group Title | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | Total of all reporting groups |
| Overall Participants | 15 | 15 | 10 | 40 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
1
6.7%
|
6
40%
|
10
100%
|
17
42.5%
|
| >=65 years |
14
93.3%
|
9
60%
|
0
0%
|
23
57.5%
|
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
71
(4)
|
68
(6)
|
31
(4)
|
61
(17)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
6
40%
|
7
46.7%
|
1
10%
|
14
35%
|
| Male |
7
46.7%
|
6
40%
|
6
60%
|
19
47.5%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
1
6.7%
|
1
10%
|
2
5%
|
| Not Hispanic or Latino |
13
86.7%
|
12
80%
|
6
60%
|
31
77.5%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
2
20%
|
2
5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
6.7%
|
2
13.3%
|
1
10%
|
4
10%
|
| White |
12
80%
|
11
73.3%
|
4
40%
|
27
67.5%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
15
100%
|
15
100%
|
10
100%
|
40
100%
|
| Exercise heart rate (beats per minute) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [beats per minute] |
156
(15)
|
117
(15)
|
190
(8)
|
148
(32)
|
| Beta-receptor function (beats per ng/kg/min) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [beats per ng/kg/min] |
0.254
(0.166)
|
0.156
(0.133)
|
0.365
(0.129)
|
0.239
(0.163)
|
Outcome Measures
| Title | Cardiac Beta-receptor Sensitivity |
|---|---|
| Description | Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level. |
| Time Frame | 1 day; primary outcome was complete for each subject in 1 day |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Healthy Seniors | HFpEF | Healthy Young |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. |
| Measure Participants | 13 | 13 | 7 |
| Mean (Standard Deviation) [beats per ng/kg/min ISO] |
0.254
(0.166)
|
0.156
(0.133)
|
0.365
(0.129)
|
| Title | Central Command Regulation of Heart Rate |
|---|---|
| Description | 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. |
| Time Frame | 1 day; primary outcome was complete for each subject in 1 day |
Outcome Measure Data
| Analysis Population Description |
|---|
| Young subjects did not perform handgrip portion of the study. |
| Arm/Group Title | Healthy Seniors | HFpEF |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 15 | 15 |
| Mean (Standard Deviation) [beats per minute] |
93
(11)
|
89
(14)
|
Adverse Events
| Time Frame | 2 years | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Healthy Seniors | HFpEF | Healthy Young | |||
| Arm/Group Description | 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. | 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. | 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. | |||
All Cause Mortality |
||||||
| Healthy Seniors | HFpEF | Healthy Young | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | 0/13 (0%) | 0/7 (0%) | |||
Serious Adverse Events |
||||||
| Healthy Seniors | HFpEF | Healthy Young | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | 0/13 (0%) | 0/7 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Healthy Seniors | HFpEF | Healthy Young | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | 0/13 (0%) | 0/7 (0%) | |||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Satyam Sarma |
|---|---|
| Organization | University of Texas Southwestern Medical Center |
| Phone | 214-345-7111 |
| SatyamSarma2@texashealth.org |
- STU 092012-010