An interventional study of Static Handgrip and Dexmedetomidine in Heart Failure, sponsored by University of Texas Southwestern Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years to 85 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-08-06.
Sponsored by University of Texas Southwestern Medical Center · Not applicable, Interventional, and Basic science
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".
5,701 studies on the registry are indexed under Heart Failure; 1,220 are open to participants now.
This study's enrollment of 40 is below the median of 72 across 3,736 interventional studies indexed under Heart Failure.
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Of its 135 completed or terminated interventional studies of FDA-regulated products, 100 (74%) have results posted.
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Healthy Controls
Inclusion Criteria:
Exclusion Criteria:
HFpEF Subjects
Inclusion Criteria:
Exclusion Criteria:
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 · Drug: Dexmedetomidine · Drug: Glycopyrrolate · Drug: Isoproterenol
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 · Drug: Dexmedetomidine · Drug: Glycopyrrolate · Drug: Isoproterenol
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 · Drug: Glycopyrrolate · Drug: Isoproterenol
Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.
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.
Also known as: 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.
Also known as: 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.
Also known as: Beta-receptor sensitivity testing
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
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
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.
| Milestone | Healthy Seniors | HFpEF | Healthy Young |
|---|---|---|---|
| Started | 15 | 15 | 10 |
| Completed | 13 | 13 | 7 |
| Not completed | 2 | 2 | 3 |
| Withdrew: Withdrawal by subject | 2 | 2 | 3 |
Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level.
| beats per ng/kg/min ISO | Healthy Seniors | HFpEF | Healthy Young |
|---|---|---|---|
| Cardiac Beta-receptor Sensitivity | 0.254 ± 0.166 | 0.156 ± 0.133 | 0.365 ± 0.129 |
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.
| beats per minute | Healthy Seniors | HFpEF |
|---|---|---|
| Central Command Regulation of Heart Rate | 93 ± 11 | 89 ± 14 |
Collected over 2 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Healthy Seniors | 0/13 (0%) | 0/13 (0%) | 0/13 (0%) |
| HFpEF | 0/13 (0%) | 0/13 (0%) | 0/13 (0%) |
| Healthy Young | 0/7 (0%) | 0/7 (0%) | 0/7 (0%) |
| Age, Categorical(Participants) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 1 | 6 | 10 | 17 |
| >=65 years | 14 | 9 | 0 | 23 |
| Age, Continuous(years) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| Mean | 71 ± 4 | 68 ± 6 | 31 ± 4 | 61 ± 17 |
| Sex: Female, Male(Participants) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| Female | 6 | 7 | 1 | 14 |
| Male | 7 | 6 | 6 | 19 |
| Ethnicity (NIH/OMB)(Participants) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 1 | 1 | 2 |
| Not Hispanic or Latino | 13 | 12 | 6 | 31 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 2 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 1 | 2 | 1 | 4 |
| White | 12 | 11 | 4 | 27 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Region of Enrollment(participants) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| United States | 15 | 15 | 10 | 40 |
| Exercise heart rate(beats per minute) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| Mean | 156 ± 15 | 117 ± 15 | 190 ± 8 | 148 ± 32 |
| Beta-receptor function(beats per ng/kg/min) | Healthy Seniors | HFpEF | Healthy Young | Total |
|---|---|---|---|---|
| Mean | 0.254 ± 0.166 | 0.156 ± 0.133 | 0.365 ± 0.129 | 0.239 ± 0.163 |
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University of Texas Southwestern Medical Center