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Chronotropic Incompetence in Patients With HFpEF

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ClinicalTrials.gov Identifier: NCT02524145
Recruitment Status : Completed
First Posted : August 14, 2015
Results First Posted : April 23, 2019
Last Update Posted : April 23, 2019
Sponsor:
Information provided by (Responsible Party):
Benjamin Levine, University of Texas Southwestern Medical Center

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
Heart Failure Other: Static Handgrip Drug: Dexmedetomidine Drug: Glycopyrrolate Drug: Isoproterenol Not Applicable

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".


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Determinants of Chronotropic Incompetence in Patients With Heart Failure and a Preserved Ejection Fraction (HFpEF)
Study Start Date : June 2015
Actual Primary Completion Date : November 15, 2017
Actual Study Completion Date : November 15, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

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 Name: Sympathetic blockade

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 Name: Parasympathetic blockade

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 Name: Beta-receptor sensitivity testing

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 Name: Sympathetic blockade

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 Name: Parasympathetic blockade

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 Name: Beta-receptor sensitivity testing

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 Name: Sympathetic blockade

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 Name: Parasympathetic blockade

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 Name: Beta-receptor sensitivity testing




Primary Outcome Measures :
  1. 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.

  2. 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.



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02524145


Locations
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United States, Texas
The Institute for Exercise and Environmental Medicine
Dallas, Texas, United States, 75231
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Investigators
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Principal Investigator: Benjamin D Levine, MD University of Texas Southwestern Medical Center
  Study Documents (Full-Text)

Documents provided by Benjamin Levine, University of Texas Southwestern Medical Center:
Study Protocol  [PDF] December 1, 2014
No Statistical Analysis Plan (SAP) exists for this study.


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Responsible Party: Benjamin Levine, Professor of Medicine, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT02524145     History of Changes
Other Study ID Numbers: UTexasSouthwestern
First Posted: August 14, 2015    Key Record Dates
Results First Posted: April 23, 2019
Last Update Posted: April 23, 2019
Last Verified: April 2019
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Isoproterenol
Glycopyrrolate
Dexmedetomidine
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adjuvants, Anesthesia
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Anti-Asthmatic Agents
Respiratory System Agents
Cardiotonic Agents
Sympathomimetics