Heart Failure
Conditions
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.
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.
Interventions
OTHERStatic Handgrip
Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.
DRUGDexmedetomidine
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.
DRUGGlycopyrrolate
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.
DRUGIsoproterenol
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.
Sponsors
University of Texas Southwestern Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 15 |
| 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. | 15 |
| 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. | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 | 3 |
Baseline characteristics
| Characteristic | Healthy Young | Healthy Seniors | HFpEF | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 14 Participants | 9 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 1 Participants | 6 Participants | 17 Participants |
| Age, Continuous | 31 years STANDARD_DEVIATION 4 | 71 years STANDARD_DEVIATION 4 | 68 years STANDARD_DEVIATION 6 | 61 years STANDARD_DEVIATION 17 |
| Beta-receptor function | 0.365 beats per ng/kg/min STANDARD_DEVIATION 0.129 | 0.254 beats per ng/kg/min STANDARD_DEVIATION 0.166 | 0.156 beats per ng/kg/min STANDARD_DEVIATION 0.133 | 0.239 beats per ng/kg/min STANDARD_DEVIATION 0.163 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 13 Participants | 12 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Exercise heart rate | 190 beats per minute STANDARD_DEVIATION 8 | 156 beats per minute STANDARD_DEVIATION 15 | 117 beats per minute STANDARD_DEVIATION 15 | 148 beats per minute STANDARD_DEVIATION 32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 12 Participants | 11 Participants | 27 Participants |
| Region of Enrollment United States | 10 participants | 15 participants | 15 participants | 40 participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 6 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 | 0 / 7 |
| other Total, other adverse events | 0 / 13 | 0 / 13 | 0 / 7 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 7 |
Outcome results
Primary
Cardiac Beta-receptor Sensitivity
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Seniors | Cardiac Beta-receptor Sensitivity | 0.254 beats per ng/kg/min ISO | Standard Deviation 0.166 |
| HFpEF | Cardiac Beta-receptor Sensitivity | 0.156 beats per ng/kg/min ISO | Standard Deviation 0.133 |
| Healthy Young | Cardiac Beta-receptor Sensitivity | 0.365 beats per ng/kg/min ISO | Standard Deviation 0.129 |
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.
Time frame: 1 day; primary outcome was complete for each subject in 1 day
Population: Young subjects did not perform handgrip portion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Seniors | Central Command Regulation of Heart Rate | 93 beats per minute | Standard Deviation 11 |
| HFpEF | Central Command Regulation of Heart Rate | 89 beats per minute | Standard Deviation 14 |