Chronotropic Incompetence in Patients With HFpEF

NCT02524145 | Completed Results DMC

• 1 other identifier: STU 092012-010
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (2)

• Cardiac Beta-receptor Sensitivity

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

  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.

  1 day; primary outcome was complete for each subject in 1 day

Study Arms (3)

Healthy Seniors

ACTIVE COMPARATOR

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

HFpEF

EXPERIMENTAL

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

Healthy Young

ACTIVE COMPARATOR

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

Interventions

Static Handgrip OTHER

Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.

HFpEF; Healthy Seniors

Dexmedetomidine DRUG

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

HFpEF; Healthy Seniors; Healthy Young

Glycopyrrolate DRUG

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

HFpEF; Healthy Seniors; Healthy Young

Isoproterenol DRUG

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

HFpEF; Healthy Seniors; Healthy Young

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• 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

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead

Study Sites (1)

The Institute for Exercise and Environmental Medicine

Dallas, Texas, 75231, United States

Location

Related Publications (1)

• 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.

  PMID: 32164435 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

Dexmedetomidine; Glycopyrrolate; Isoproterenol

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals; Onium Compounds; Pyrrolidines; Ethanolamines; Amino Alcohols; Alcohols; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Results Point of Contact

• Title: Dr. Satyam Sarma
• Organization: University of Texas Southwestern Medical Center

SatyamSarma2@texashealth.org

214-345-7111

Study Officials

• Benjamin D Levine, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: August 10, 2015
• First Posted: August 14, 2015
• Study Start: June 1, 2015
• Primary Completion: November 15, 2017
• Study Completion: November 15, 2017
• Last Updated: August 6, 2020
• Results First Posted: April 23, 2019

Record last verified: 2020-08

Locations

US (1)