Chronotropic Incompetence in Patients With HFpEF

Not Applicable

Completed

• Conditions: Heart Failure
• Interventions: Other: Static Handgrip; Drug: Dexmedetomidine; Drug: Glycopyrrolate; Drug: Isoproterenol

• Registration Number: NCT02524145
• Lead Sponsor: 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.

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".

Study Timeline

• Study Start: 2015-06
• Study First Submitted: 2015-08-10
• Study First Submitted QC: 2015-08-12
• Study First Posted: 2015-08-14
• Primary Completion: 2017-11-15
• Study Completion: 2017-11-15
• Results First Submitted: 2018-12-18
• Results First Submitted QC: 2019-04-04
• Results First Posted: 2019-04-23
• Status Verified: 2020-08
• Last Update Submitted: 2020-08-04
• Last Update Posted: 2020-08-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Healthy Seniors	Static Handgrip	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)
Healthy Young	Glycopyrrolate	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)
Healthy Young	Dexmedetomidine	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)
HFpEF	Static Handgrip	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)
Healthy Seniors	Dexmedetomidine	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)
HFpEF	Dexmedetomidine	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)
Healthy Seniors	Glycopyrrolate	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)
HFpEF	Glycopyrrolate	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)
Healthy Seniors	Isoproterenol	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)
HFpEF	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)
Healthy Young	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)

Primary Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (1)

The Institute for Exercise and Environmental Medicine; 🇺🇸 Dallas, Texas, United States