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Chronotropic Incompetence in Patients With HFpEF

Primary Purpose

Heart Failure

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Static Handgrip
Dexmedetomidine
Glycopyrrolate
Isoproterenol
Sponsored by
University of Texas Southwestern Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Heart Failure

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • The Institute for Exercise and Environmental Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Active Comparator

Arm Label

Healthy Seniors

HFpEF

Healthy Young

Arm 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)

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)

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)

Outcomes

Primary Outcome Measures

Cardiac Beta-receptor Sensitivity
Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level.
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.

Secondary Outcome Measures

Full Information

First Posted
August 10, 2015
Last Updated
August 4, 2020
Sponsor
University of Texas Southwestern Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT02524145
Brief Title
Chronotropic Incompetence in Patients With HFpEF
Official Title
Determinants of Chronotropic Incompetence in Patients With Heart Failure and a Preserved Ejection Fraction (HFpEF)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
June 2015 (undefined)
Primary Completion Date
November 15, 2017 (Actual)
Study Completion Date
November 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Texas Southwestern Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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".

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Healthy Seniors
Arm Type
Active Comparator
Arm 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)
Arm Title
HFpEF
Arm Type
Experimental
Arm Description
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)
Arm Title
Healthy Young
Arm Type
Active Comparator
Arm Description
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)
Intervention Type
Other
Intervention Name(s)
Static Handgrip
Intervention Description
Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.
Intervention Type
Drug
Intervention Name(s)
Dexmedetomidine
Other Intervention Name(s)
Sympathetic blockade
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Glycopyrrolate
Other Intervention Name(s)
Parasympathetic blockade
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Isoproterenol
Other Intervention Name(s)
Beta-receptor sensitivity testing
Intervention Description
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.
Primary Outcome Measure Information:
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Benjamin D Levine, MD
Organizational Affiliation
University of Texas Southwestern Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Institute for Exercise and Environmental Medicine
City
Dallas
State/Province
Texas
ZIP/Postal Code
75231
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
32164435
Citation
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.
Results Reference
derived

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Chronotropic Incompetence in Patients With HFpEF

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